Alpha-(n-sulfonamido)acetamide derivatives as beta-amyloid inhibitors

ABSTRACT

There is provided a series of novel α-(N-sulfonamido)acetamide compounds of the Formula (I)  
                 
 
wherein R, R 1 , R 2  and R 3  are defined herein, which are inhibitors of β-amyloid peptide (β-AP) production and are useful in the treatment of Alzheimer&#39;s Disease and other conditions affected by anti-amyloid activity.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a non-provisional application which claims the benefit of U.S.Provisional Application No. 60/344,322 filed Dec. 20, 2001.

FIELD OF THE INVENTION

This invention provides novel α-(N-sulfonamido)acetamide compoundshaving drug and bio-affecting properties, their pharmaceuticalcompositions and method of use. In particular, the invention isconcerned with α-(N-arylsulfonamido)acetamides. These compounds possessunique inhibition of the β-amyloid peptide (β-AP) production, therebyacting to prevent the accumulation of amyloid protein deposits in thebrain. More particularly, the present invention relates to the treatmentof Alzheimer's Disease (AD).

BACKGROUND OF THE INVENTION

Alzheimer's Disease is a progressive, neurodegenerative disordercharacterized by memory impairment and cognitive dysfunction. AD ischaracterized pathologically by the accumulation of senile (neuritic)plaques, neurofibrillary tangles, amyloid deposition in neural tissuesand vessels, synaptic loss, and neuronal death. It is the most commonform of dementia and it now represents the third leading cause of deathafter cardiovascular disorders and cancer. The cost of Alzheimer'sDisease is enormous (in the U.S., greater than $100 billion annually)and includes the suffering of the patients, the suffering of families,and the lost productivity of patients and caregivers. As the longevityof society increases, the occurrence of AD will markedly increase. It isestimated that more than 10 million Americans will suffer from AD by theyear 2020, if methods for prevention and treatment are not found.Currently, AD is estimated to afflict 10% of the population over age 65and up to 50% of those over the age of 85. No treatment that effectivelyprevents AD or reverses the clinical symptoms and underlyingpathophysiology is currently available (for review see Selkoe, D. J.Ann. Rev. Cell Biol., 1994, 10: 373-403).

There have been many theories relating to the etiology and pathogenesisof AD. These theories were either based on analogies with other diseasesand conditions (e.g., slow virus and aluminum theories), or based onpathologic observations (e.g., cholinergic, amyloid, or tangletheories). Genetic analysis can potentially differentiate betweencompeting theories. The identification of mutations in the β-amyloidprecursor protein (β-APP) of individuals prone to early onset forms ofAD and related disorders strongly supports the amyloidogenic theories.

Histopathological examination of brain tissue derived upon autopsy orfrom neurosurgical specimens in affected individuals reveals theoccurrence of amyloid plaques and neurofibrillar tangles in the cerebralcortex of such patients. Similar alterations are observed in patientswith Trisomy 21 (Down's syndrome). Biochemical and immunological studiesreveal that the dominant proteinaceous component of the amyloid plaqueis an approximately 4.2 kilodalton (kD) protein of about 39 to 43 aminoacids. This protein is designated Aβ, β-amyloid peptide, and sometimesβ/A4; referred to herein as Aβ. In addition to its deposition in amyloidplaques, Aβ is also found in the walls of meningeal and parenchymalarterioles, small arteries, capillaries, and sometimes, venules.Compelling evidence accumulated during the last decade reveals that Aβis an internal polypeptide derived from a type 1 integral membraneprotein, termed β-amyloid precursor protein (APP) (Selkoe, D. Physiol.Rev. 2001, 81, 741-766; Wolfe, M. J. Med. Chem. 2001, 44, 2039-2060).βAPP is normally produced by many cells both in vivo and in culturedcells, derived from various animals and humans. Several proteolyticfragments of APP are generated by proteinases referred to as secretases.A subset of these proteolytic fragments, designated β-amyloid peptide(Aβ), contains 39 to 43 amino acids and is generated by the combinedaction of β-secretase and γ-secretase. β-secretase is a membrane-bound,aspartyl protease that forms the N-terminus of the Aβ peptide. TheC-terminus of the Aβ peptide is formed by γ-secretase, an apparentlyoligomeric complex that includes presenilin-1 and/or presenilin-2.Presenilin-1 and presenilin-2 are polytopic membrane-spanning proteinsthat may contain the catalytic components of γ-secretase (Seiffert, D.;Bradley, J. et al. J. Biol. Chem. 2000, 275, 34086-34091).

Multiple lines of evidence together strongly suggest that a reduction inbrain Aβ levels will prevent the onset and progression of AD. First, Aβis a major constituent of the parenchemyal plaques observed in all ADpatients and the cerebral vasculature amyloid deposits observed in 90%AD patients (reviewed in Selkoe, D. Physiol. Rev. 2001, 81, 741-766;Wolfe, M. J. Med. Chem. 2001, 44, 2039-2060). These plaques are formedfrom the aggregation of soluble Aβ whose brain levels are highlycorrelated with the severity of AD neurodegeneration (McLean, C., Chemy,R. et al. Ann. Neurol. 1999, 46, 860-866). Second, mutations in threegenes (APP, PS-1, or PS-2) that increase Aβ cause familial AD (FAD),where AD onset is accelerated by at least a decade. Included in themutations that increase Aβ are chromosome 21 Trisomy that causes Down'ssyndrome. Third, transgenic mice that express one or more of the mutantFAD genes have increased Aβ levels, form parenchymal plaques andcerebral vascular deposits containing Aβ, exhibit memory deficits(Chapman, P.; White, G. et al. Nature Neurosci. 1999, 2, 271-276) andenhance neurofibrillary degeneration in mice that also overexpressmutant tau (Lewis, J.; Dickson, D. et al. Science 2001, 293, 1487-1491).Fourth, Aβ is toxic to cultured cells (Dahlgren, K.; Manelli, A. et al.J. Biol. Chem. 2002 277, 32046-32053), induces neurofibrillary tanglesin mice with mutant tau (Gotz, J., Chen, F. et al. Science 2001, 293,1491-1495) and interferes with long-term potentiation, a likelycomponent of memory (Walsh, D., Klyubin, I. et al. Nature 2002, 416,535-539 and references therein). Taken together, these data lead oneskilled in the art to conclude that excess Aβ production and/or reducedAβ clearance cause AD. From this it follows that reducing brain Aβlevels by inhibition of γ-secretase will prevent the onset andprogression of AD.

In addition to AD, excess production and/or reduced clearance of Aβcauses cerebral amyloid angiopathy (CAA) (reviewed in Thal, D.,Gherbremedhin, E. et al. J. Neuropath. Exp. Neuro. 2002, 61, 282-293).In these patients, vascular amyloid deposits cause degeneration ofvessel walls and aneurysms that may be responsible for 10-15%hemorrhagic strokes in elderly patients. As in AD, mutations in the geneencoding Aβ lead to an early onset form of CAA, referred to as cerebralhemorrhage with amyloidosis of the Dutch type, and mice expressing thismutant protein develop CAA that is similar to patients.

It is hypothesized that inhibiting the production of Aβ will prevent andreduce neurological degeneration, reducing neurotoxicity and, generally,mediating the pathology associated with Aβ production. Methods oftreatment could target the formation of Aβ through the enzymes involvedin the proteolytic processing of β-amyloid precursor protein. Compoundsthat inhibit β- or γ-secretase activity, either directly or indirectly,could control the production of Aβ. Advantageously, compounds thatspecifically target γ-secretases, could control the production of Aβ.Such inhibition of β- or γ-secretases could thereby reduce production ofAβ which, could reduce or prevent the neurological disorders associatedwith Aβ protein.

Smith, et al. in International Application WO 00/50391, published Aug.31, 2000, disclose a series of sulfonamide compounds that can act tomodulate production of amyloid β protein as a means of treating avariety of diseases, especially Alzheimer's Disease and other diseasesrelating to the deposition of amyloid. Japanese Patent No. 11343279,published Dec. 14, 1999 discloses a series of sulfonamide derivativeswhich are TNF-alpha inhibitors useful for treating autoimmune diseases.

Nothing in these references can be construed to disclose or suggest thenovel compounds of this invention and their use to inhibit β-APproduction.

SUMMARY OF THE INVENTION

A series of α-(N-sulfonamido)acetamide derivatives have beensynthesized. These compounds specifically inhibit the production ofβ-amyloid peptide (β-AP) from β-amyloid precursor protein (β-APP). Thepharmacologic action of these compounds makes them useful for treatingconditions responsive to the inhibition of β-AP in a patient; e.g.,Alzheimer's Disease (AD) and Down's Syndrome. Therapy utilizingadministration of these compounds to patients suffering from, orsusceptible to, these conditions involves reducing β-AP available foraccumulation and deposition in brains of these patients.

DETAILED DESCRIPTION OF THE INVENTION

The present invention comprises compounds of Formula I, theirpharmaceutical formulations, and their use in inhibiting β-AP productionin patients suffering from or susceptible to AD or other disordersresulting from β-AP accumulation in brain tissue. The compounds ofFormula I which include nontoxic pharmaceutically acceptable saltsand/or hydrates thereof have the following formula and meanings:

wherein:

-   R¹ is selected from the group consisting of    -   (a) a straight or branched-chain C₁₋₆ alkyl or C₂₋₆alkenyl        optionally substituted with substituents selected from the group        consisting of hydroxy, C₃₋₇ cycloalkyl, C₁₋₄alkoxy,        C₁₋₄alkylthio, and halogen;    -   (b) C₃₋₇ cycloalkyl optionally substituted with hydroxy or        halogen;-   R is hydrogen or R¹ and R taken together is C₂₋₅alkylene;-   R² is selected from the group consisting of    -   (a) a straight or branched-chain C₁₋₆alkyl or C₃₋₆alkenyl        optionally substituted with substituents selected from the group        consisting of halogen, C₁₋₄alkoxy, and NR⁴R⁵;    -   (b) C₃₋₇ cycloalkylmethyl optionally substituted with        substituents selected from the group consisting of amino,        (C₁₋₄alkyl)NH—, di(C₁₋₄alkyl)N—, C₁₋₄alkylC(═O)NH—, and        C₁₋₄alkylOC(═O)NH—;    -   (c) a straight or branched-chain C₁₋₆alkyl-C(═O)-A;    -   (d) —B-naphthyl;    -   (e)        -   D and E are each independently a direct bond, a straight or            branched-chain C₁₋₆alkyl, C₂₋₆ alkenyl, or C₃₋₇ cycloalkyl;        -   Z is selected from the group consisting of hydrogen,            C₁₋₄alkyl, C₁₋₄alkoxy, halogen, cyano, hydroxy, —OCHF₂,            —OCF₃, —CF₃, and —CHF₂;        -   X and Y are each independently selected from the group            consisting of hydrogen, hydroxy, halogen, (halogen)₃C—,            (halogen)₂CH—, C₁₋₄alkylS—, C₁₋₄alkylS(O)—, C₁₋₄alkylSO₂—,            nitro, F₃S—, and cyano; —OR⁶; —NR⁴R⁵; —NR⁷C(═O)R⁸;            —NR⁷C(═O)OR⁸; —NHSO₂C₁₋₄alkyl; —N(SO₂C₁₋₄alkyl)₂; —C(═O)W            wherein W is selected from the group consisting of hydroxy,            C₁₋₄alkyl, C₁₋₄alkoxy, phenoxy, and —NR⁴R⁵;            —OC(═O)C₁₋₄alkyl; -phenyl in which said phenyl is optionally            substituted with cyano, halogen, C₁₋₄alkoxy, C₁₋₄alkylS—,            CH₃C(═O), C₁₋₄alkylS(O)—, or C₁₋₄alkylSO₂—; and heterocyclic            group, in which said heterocyclic group is selected from the            group consisting of furanyl, thiofuranyl, pyrrolyl,            imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl,            pyrimidinyl, oxadiazolyl, oxazolyl, isoxazolyl,            thiadiazolyl, and thiazolyl, wherein said heterocyclic group            is optionally substituted with substituents selected from            the group consisting of cyano, halogen, C₁₋₄alkyl,            (halogen)C₁₋₄alkyl, and CO₂C₁₋₄alkyl;    -   (f) —B-(heterocycle), in which said heterocycle is selected from        the group consisting of furanyl, thiofuranyl, pyrrolyl,        imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl,        pyrimidinyl, oxadiazolyl, oxazolyl, isoxazolyl, thiadiazolyl and        thiazolyl wherein said heterocycle is optionally substituted        with substituents selected from the group consisting of cyano,        halogen, C₁₋₄alkyl, CO₂C₁₋₄alkyl, amino, (C₁₋₄alkyl)NH—,        di(C₁₋₄alkyl)N—, morpholin-4-yl, thiomorpholin-4-yl,        pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, and        4-(C₁₋₆alkyl)piperazin-1-yl;    -   (g) —B-(piperidin-4-yl), in which said piperidin-4-yl is        optionally substituted with substituents selected from the group        consisting of a straight or branched-chain C₁₋₆alkyl,        CH₂C(═O)phenyl, phenyl and phenylmethyl in which said C₁₋₆alkyl        and said phenyl are optionally substituted with substituents        selected from the group consisting of cyano, halogen,        benzimidazol-2-yl, pyridyl and tetrahydrofuran-2-yl; and        —C(═O)W′ wherein W′ is selected from the group consisting of        C₁₋₄alkoxy, R⁹, and —NR⁴R⁵;-   A is hydroxy, C₁₋₄alkoxy or NR⁴R⁵;-   B is a straight or branched-chain C₁₋₆alkyl or C₃₋₆alkenyl;-   R³ is phenyl or pyridyl optionally substituted with substituents    selected from the group consisting of halogen, hydroxy, C₁₋₄alkoxy,    C₁₋₄alkyl, (halogen)₃C—, (halogen)₂CH—, and halogenCH₂—;-   R⁴ and R⁵ each are independently hydrogen, a straight or    branched-chain C₁₋₆ alkyl, C₃₋₆ alkenyl, C₃₋₆ alkynyl, C₃₋₇    cycloalkyl, C₃₋₇ cycloalkylmethyl, C₁₋₄alkoxy, phenyl, benzyl,    pyridyl, piperidin-4-yl, indan-1-yl, indan-2-yl,    tetrahydrofuran-3-yl, or pyrrolidin-3-yl; in which each is    optionally substituted with substituents selected from the group    consisting of hydroxy, cyano, halogen, (halogen)₃C—, (halogen)₂CH—,    halogenCH₂—, hydroxymethyl, benzyloxymethyl, phenyl, pyridyl,    C₁₋₄alkyl, C₁₋₄alkoxy, (halogen)₃C—O—, (halogen)₂CH—O—,    C₁₋₄alkylthio, amino, (C₁₋₄alkyl)NH—, di(C₁₋₄alkyl)N—,    morpholin-4-yl, thiomorpholin-4-yl, pyrrolidin-1-yl, piperidin-1-yl,    piperazin-1-yl, 4-(C₁₋₆alkyl)piperazin-1-yl, 4-phenylpiperazin-1-yl,    4-benzylpiperazin-1-yl, 4-pyridylpiperazin-1-yl, CO₂H, CO₂C₁₋₄alkyl,    C(═O)NHC₁₋₄alkyl, and C(═O)N(C₁₋₄alkyl)₂;-   R⁴ and R⁵ taken together may be morpholin-4-yl, thiomorpholin-4-yl,    pyrrolidin-1-yl, 1,2,3,4-tetrahydroisoquinolin-2-yl,    decahydroquinolin-1-yl, piperidin-1-yl, piperazin-1-yl,    [1,4]-oxazepan-4-yl, azetidin-1-yl, 2,3-dihydro-1H-isoindol-2-yl, or    2,3-dihydro-1H-indol-1-yl; in which each is optionally substituted    with substituents selected from the group consisting of hydroxy,    cyano, halogen, (halogen)₃C—, (halogen)₂CH—, halogenCH₂—, phenyl,    pyridyl, benzyl, C₁₋₆alkyl, C₃₋₇ cycloalkyl, C₁₋₄alkoxy,    C₁₋₄alkylthio, amino, (C₁₋₄alkyl)NH—, di(C₁₋₄alkyl)N—, CO₂H,    CO₂C₁₋₄alkyl, C(═O)NHC₁₋₄alkyl, and C(═O)N(C₁₋₄alkyl)₂;-   R⁶ is a straight or branched-chain C₁₋₆alkyl, C₃₋₆ alkenyl, benzyl,    or phenyl in which each is optionally substituted with substituents    selected from the group consisting of halogen, C₁₋₄alkyl,    C₁₋₄alkoxy, amino, (C₁₋₄alkyl)NH—, di(C₁₋₄alkyl)N—,    (C₁₋₄alkyl)(phenyl)N—, morpholin-4-yl, thiomorpholin-4-yl,    pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, and    4-(C₁₋₆alkyl)piperazin-1-yl;-   R⁷ is hydrogen, a straight or branched-chain C₁₋₆ alkyl;-   R⁸ is a straight or branched-chain C₁₋₆alkyl, C₃₋₇ cycloalkyl,    phenyl, pyridyl, or furanyl; in which each is optionally substituted    with substituents selected from the group consisting of halogen,    C₁₋₄alkyl, C₁₋₄alkoxy, (C₁₋₄alkyl)NH—, di(C₁₋₄alkyl)N—,    morpholin-4-yl, thiomorpholin-4-yl, pyrrolidin-1-yl, piperidin-1-yl,    piperazin-1-yl, and 4-(C₁₋₆alkyl)piperazin-1-yl;-   R⁹ is a straight or branched-chain C₁₋₆alkyl, C₃₋₆ alkenyl, benzyl,    phenyl, oxazolyl or pyridyl; in which each is optionally substituted    with substituents selected from the group consisting of halogen,    (halogen)₃C—, (halogen)₂CH—, halogenCH₂—, C₁₋₄alkyl, C₁₋₄alkoxy,    amino, (C₁₋₄alkyl)NH—, di(C₁₋₄alkyl)N—, morpholin-4-yl,    thiomorpholin-4-yl, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl,    and 4-(C₁₋₆alkyl)piperazin-1-yl;    or a non-toxic pharmaceutically acceptable salt thereof.

The present invention also provides a method for the treatment oralleviation of disorders associated with β-amyloid peptide, especiallyAlzheimer's Disease, which comprises administering together with aconventional adjuvant, carrier or diluent a therapeutically effectiveamount of a compound of formula I or a nontoxic pharmaceuticallyacceptable salt, solvate or hydrate thereof.

The term “C₁₋₆ alkyl” as used herein and in the claims (unless thecontext indicates otherwise) means straight or branched chain alkylgroups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,t-butyl, pentyl, 3-methylbutyl, hexyl and the like. The term “C₂₋₆alkenyl” used herein and in the claims (unless the context indicatesotherwise) means straight or branched chain alkenyl groups such asethenyl (i.e. vinyl), propenyl, allyl, butenyl, 3-methylbutenyl,pentenyl, hexenyl and the like. Unless otherwise specified, the term“halogen” as used herein and in the claims is intended to includebromine, chlorine, iodine and fluorine while the term “halide” isintended to include bromide, chloride and iodide anion.

The term “C₃₋₇ cycloalkyl” means a carbon cyclic ring system such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

The term “C₁₋₄ haloalkyl” means a straight or branched chain C₁₋₄ alkylgroup containing from 1 to 3 halogen atoms such as trifluoromethyl,fluoroethyl, 1,2-dichloroethyl, trichloroethyl and the like.

The term “C₂₋₅ alkylene” means a straight or branched chain alkylenegroup such as methylene, ethylene, propylene, methylethylene, butylene,methylpropylene, pentylene, methylbutylene and ethylpropylene.

As the compounds of the present invention possess an asymmetric carbonatom, the present invention includes the racemate as well as theindividual enantiometric forms of the compounds of Formula I asdescribed herein and in the claims. The use of a single designation suchas (R) or (S) is intended to include mostly one stereoisomer. Mixturesof isomers can be separated into individual isomers according to methodswhich are known per se, e.g. fractional crystallization, adsorptionchromatography or other suitable separation processes. Resultingracemates can be separated into antipodes in the usual manner afterintroduction of suitable salt-forming groupings, e.g. by forming amixture of diastereosiomieric salts with optically active salt-formingagents, separating the mixture into diastereomeric salts and convertingthe separated salts into the free compounds. The possible enantiomericforms may also be separated by fractionation through chiral highpressure liquid chromatography columns.

The term “nontoxic pharmaceutically acceptable salt” as used herein andin the claims is intended to include nontoxic base addition salts.Suitable salts include those derived from organic and inorganic acidssuch as, without limitation, hydrochloric acid, hydrobromic acid,phosphoric acid, sulfuric acid, methanesulfonic acid, acetic acid,tartaric acid, lactic acid, sulfinic acid, citric acid, maleic acid,fumaric acid, sorbic acid, aconitic acid, salicylic acid, phthalic acid,and the like.

In the method of the present invention, the term “therapeuticallyeffective amount” means the total amount of each active component of themethod that is sufficient to show a meaningful patient benefit, i.e.,healing of acute conditions characterized by inhibition of β-amyloidpeptide production. When applied to an individual active ingredient,administered alone, the term refers to that ingredient alone. Whenapplied to a combination, the term refers to combined amounts of theactive ingredients that result in the therapeutic effect, whetheradministered in combination, serially or simultaneously. The terms“treat, treating, treatment” as used herein and in the claims meanspreventing or ameliorating diseases associated with β-amyloid peptide.

General Reaction Schemes

The general procedures used to synthesize the compounds of Formula I aredescribed in Reaction Schemes 1-23. Reasonable variations of thedescribed procedures, which would be evident to one skilled in the art,are intended to be within the scope of the present invention.

The starting (α-amino)acetamides of Formula II are used in racemic or inenantiomerically pure form and are commercially available or areprepared by well-known literature procedures from commercially available(α-amino)acids (general reference for amide preparation.: R. C. Larock“Comprehensive Organic Transformations, VCH Publishers, New York, 1989,pp. 972-976; see also Reaction Scheme 18 for the conversion of the acidof Formula XLVIII to the amide of Formula XLIX). The compound of FormulaII is treated with a suitable base and a sulfonylating reagent such as asulfonyl chloride in an aprotic solvent such as CH₂Cl₂ at roomtemperature to generate the (α-sulfonamido)acetamide of Formula III.Suitable bases include triethylamine and pyridine.

In one method for conversion of the compound of Formula III to thesulfonamide of Formula I, the compound of Formula III is treated with asuitable base and an alkylating agent in an aprotic solvent with orwithout heating. Suitable bases for this reaction include potassiumcarbonate and cesium carbonate. Alkylating agents include alkyl halides(e.g., alkyl chloride, alkyl bromide, or alkyl iodide) and alkylsulfonates (tosylates, mesylates, trifluoromethanesulfonates). Preferredsolvents include DMF and acetonitrile. The temperature range for thereaction is typically 20° C. to 100° C.

An alternative method for conversion of the compound of Formula III tothe compound of Formula I involves treatment of the compound of FormulaIII with triphenyl phosphine, a dialkyl azodicarboxylate, and an alcoholin an inert solvent with or without heating.

The compounds of Formula I can also be prepared using solid phasemethodology. For example, FMOC-protected Rink amide resin is treatedwith piperidine in DMF to effect removal of the FMOC group. The resin isthen coupled with an amino-protected (α-amino)acid in the presence of acoupling agent such as 1-hydroxybenzotriazole and a dialkyl carbodiimidein an inert solvent such as DMF with or without heating. Deprotection ofthe α-amino group affords the polymer-bound amide of Formula IV. In thecase of an FMOC-protected amino acid, the deprotection can beaccomplished by treatment with piperidine in DMF.

Reaction of the compound of Formula IV with an appropriate base such aspyridine and a sulfonylating agent such as a sulfonyl chloride in aninert solvent provides the resin-linked sulfonamide of Formula V.Alkylation of the compound of Formula V with an alkyl halide (e.g.,alkyl chloride, alkyl bromide, or alkyl iodide) or alkyl sulfonate(e.g., mesylate, tosylate, or trifluoromethanesulfonate) is carried outin the presence of a base in an inert solvent at room temperature. Apreferred base is2-t-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diasaphosphorine.Cleavage from the resin provides the sulfonamide of Formula I. In thecase of the Rink amide resin, the cleavage is preferably carried outusing trifluoroacetic acid in an inert solvent such as CH₂Cl₂.

The compounds of Formula I can also be prepared as shown in ReactionScheme 2. Reductive alkylation of the amine of Formula I to provide theamine of Formula VI is effected by treatment with an aldehyde and ahydride reducing agent in the presence of an acid catalyst with orwithout heating. A preferred reducing agent is sodium cyanoborohydride.A preferred acid catalyst is a Lewis acid such as ZnCl₂. The reactionsolvent is preferably methanol. The amine of Formula VI is then treatedwith a sulfonylating agent such as a sulfonyl chloride in the presenceof an amine such as triethylamine. This reaction is carried out in aninert solvent such as CH₂Cl₂ with or without heating to afford theproduct of Formula I. The reaction is typically carried out at roomtemperature.

Preparation of compounds of Formula VIII is accomplished as shown inReaction Scheme 3 by reaction of the compound of Formula VII with anamine in the presence of an acid scavenger such as triethylamine in aninert solvent such as CH₂Cl₂ with or without heating. The compound ofFormula VII is prepared by the sequence shown in Reaction Scheme 1 orReaction Scheme 2.

The compounds of Formula XI and XII are prepared as shown in ReactionScheme 4. Reduction of the nitro group of the compound of Formula IX(prepared by the sequence shown in Reaction Scheme 1 or 2) with hydrogengas under pressure in the presence of a palladium catalyst, acid, and ina solvent such as methanol provided the aniline derivative of Formula X.Monomethylation of the compound of Formula X to provide the compound ofFormula XI is accomplished by reaction with 1.1 equivalents of a methylhalide or a methyl sulfonate, for example dimethylsulfate, in thepresence of a base such as triethylamine and in an inert solvent such asDMF. The monomethylation reaction is typically carried out between 20°C. and 40° C. Preparation of the dimethylaniline of Formula XII iseffected by treatment of the aniline of Formula X with an excess of amethyl halide such as methyl iodide or a methyl sulfonate in thepresence of a base, for example cesium carbonate, in a solvent such asDMF, with or without heating.

Reaction Scheme 5 outlines the synthesis of esters of Formula XIII,acids of Formula XIV, and amides of Formula XV. Reaction of a compoundof Formula III with a haloalkylcarboxylate ester, for example t-butylbromoacetate, in the presence of a base such as potassium carbonate andin an inert solvent such as DMF affords the ester of Formula XIII.Deprotection of the ester is effected by methods known to those skilledin the art (ref.: T. W. Greene and P. G. M. Wuts, “Protecting Groups inOrganic Synthesis”, Wiley Interscience, New York, 1999, pp 373-442). Forexample, for t-butyl esters, cleavage to the acid of Formula XIV isaccomplished by treatment with trifluoroacetic acid in a solvent such asCH₂Cl₂. Conversion of the acid to the amide of Formula XV is carried outusing common amide coupling procedures well known to those skilled inthe art (ref.: R. C. Larock “Comprehensive Organic Transformations, VCHPublishers, New York, 1989, pp. 972-976). In a preferred procedure, theacid of Formula XIV is treated with a primary or secondary amine in thepresence of 1-hydroxybenzotriazole and 1,3-dicyclohexylcarbodiimide inan aprotic solvent such as CH₂Cl₂ or DMF.

The preparation of acids of Formula XVII and amides of Formula XVIII isshown in Reaction Scheme 6. Conversion of an ester of Formula XVI(prepared as shown in Reaction Schemes 1 or 2) to an acid of FormulaXVII is accomplished using standard ester cleavage conditions well knownto those skilled in the art (ref: T. W. Greene and P. G. M. Wuts,“Protecting Groups in Organic Synthesis”, Wiley Interscience, New York,1999, pp. 373-442). In the case of a methyl ester of Formula XVI,treatment with aqueous sodium hydroxide in a solvent such a methanol ora methanol/THF mixture at 20° C. to 40° C. provides the acid of FormulaXVII. Conversion of the acid of Formula XVII to the amide of FormulaXVIII is achieved using common amide coupling procedures well known tothose skilled in the art (ref.: R. C. Larock “Comprehensive OrganicTransformations, VCH Publishers, New York, 1989, pp. 972-976). In apreferred procedure, the acid of Formula XVII is treated with a primaryor secondary amine in the presence of 1-hydroxybenzotriazole and acarbodiimide, for example 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide,in a solvent such as DMF or CH₂Cl₂. A base such a diisopropylethylaminecan be added as an acid scavenger.

The synthesis of piperidine derivatives of Formula XIX, XX, XXI, XXII,and XXIII is described in Reaction Scheme 7. Reaction of a compound ofFormula III with an N-protected piperidine substituted with a4-haloalkyl or 4-sulfonyloxyalkyl group, such as4-(toluenesulfonyloxymethyl)-1-(t-butoxycarbonyl)piperidine, in thepresence of a base such as cesium carbonate in a solvent such as DMF,with or without heating, provides the carbamate of Formula XIX. Cleavageof the carbamate group in the compound of Formula XIX is carried outunder standard conditions well known to those skilled in the art (ref.:T. W. Greene and P. G. M. Wuts, “Protecting Groups in OrganicSynthesis”, Wiley Interscience, New York, 1999, pp. 503-550) to providethe piperidine of Formula XX. In the case of a(t-butoxycarbonyl)piperidine derivative, the cleavage is effected bytreatment with trifluoroacetic acid in CH₂Cl₂.

Conversion of the piperidine of Formula XX to an amide of Formula XXI iscarried out using amide-coupling procedures well known to those skilledin the art (ref.: R. C. Larock “Comprehensive Organic Transformations,VCH Publishers, New York, 1989, pp. 972-976). In a preferred method, thepiperidine of Formula XX is treated with an acyl chloride in thepresence of an amine such as triethylamine and in an inert solvent suchas CH₂Cl₂ with or without heating. Alternatively, the piperidine ofFormula XX may be coupled with an acid in the presence of couplingagents such as hydroxybenzotriazole and a carboduimide to provide anamide of Formula XXI. Preparation of the urea of Formula XXII isachieved by treatment of the amine of Formula XX with an isocyanate anda base such as triethylamine in a solvent such as CH₂Cl₂ with or withoutheating. Alkylation of the piperidine of Formula XX providesN-substituted piperidines of Formula XXIII. In a typical procedure, thepiperidine is treated with an alkyl halide or an alkyl sulfonate in thepresence of a base such as triethylamine and in a solvent such asCH₂Cl₂.

Alcohols of Formula XXV and amines of Formula XXVI are synthesized bythe sequence shown in Reaction Scheme 8. A protected alcohol of FormulaXXIV is prepared by the procedure shown in Reaction Schemes 1 or 2.Deprotection of the alcohol under the appropriate conditions for thechosen protecting group (ref.: T. W. Greene and P. G. M. Wuts,“Protecting Groups in Organic Synthesis”, Chapter 2) provides thealcohol of Formula XXV. For example, when the protecting group is atetrahydropyranyl moiety, the alcohol is liberated by treatment of thecompound of Formula XXIV with p-toluenesulfonic acid in a solvent suchas methanol. The alcohol of Formula XXV is converted to a leaving group(e.g., a halide or sulfonate) and then treated with a primary orsecondary amine to afford an amine of Formula XXVI. For example, thealcohol may be converted to a mesylate derivative by reaction withmethanesulfonyl chloride and a base such as triethylamine in CH₂Cl₂.Subsequent reaction of the mesylate with a primary or secondary amine inthe presence of a base such as triethylanine in a solvent such as CH₂Cl₂provides the amine of Formula XXVI.

Amides of Formula XXVIII are prepared from amines of Formula XXVII asshown in Reaction Scheme 9. Amines of Formula XXVII wherein D is adirect bond are prepared as in Reaction Scheme 1 or 4. Amines of FormulaXXVII wherein D is other than a direct bond are prepared as in ReactionScheme 8. Conversion of the amines of Formula XXVII to the amides ofFormula XXVIII is carried out using amide-coupling conditions well knownto those skilled in the art (ref.: R. C. Larock “Comprehensive OrganicTransformations, VCH Publishers, New York, 1989, pp. 972-976). Forexample, reaction of the amine of Formula XXVII with an acid chloride inthe presence of a base such as triethylamine in a solvent such as CH₂Cl₂provides the amide of Formula XXVIII. Conversion of the amines ofFormula XXVII to carbamate derivatives can be carried out usingconditions well known to those skilled in the art. (ref.: T. W. Greeneand P. G. M. Wuts, “Protecting Groups in Organic Synthesis”, P.503-550). Preparation of sulfonamide derivatives from an amine ofFormula XXVII can also be achieved using methods such as that describedfor the conversion of the intermediate of Formula II to the sulfonamideof Formula III.

The synthesis of pyridine derivatives of Formula XXX is accomplished asshown in Reaction Scheme 10. The chloropyridine derivative of FormulaXXIX is prepared using the chemistry described in Reaction Schemes 1 or2. Treatment of the compound of Formula XXIX with a primary or secondaryamine in a solvent such as THF at temperatures from 20° C. to 100° C.,using sealed, pressurized vessel as appropriate, provides theaminopyridine of Formula XXX.

Amine-substituted phenol ethers of Formula XXXII are prepared from(O-allyl)phenols as indicated in Reaction Scheme 11. The starting allylethers of Formula XXXI are prepared as shown in Reaction Schemes 1 or 2.Treatment of the compound of Formula XXXI with osmium tetroxide andtrimethylamine N-oxide in a solvent such as acetone followed bytreatment with sodium periodate gives an intermediate aldehyde that istypically used without purification. Reaction of the unpurified aldehydewith a primary or secondary amine and a reducing agent such as sodiumtriacetoxyborohydride in a solvent such as ethanol with or withoutheating affords the amine of Formula XXXII.

Conversion of the ester of Formula XXXIII to the tertiary alcohol ofFormula XXXIV is carried out as shown in Reaction Scheme 12. Reaction ofthe ester of Formula XXXIII with an excess of a methyl organometallicreagent such as methyl magnesium bromide in a solvent such as THF at atemperature ranging from 0° C. to 25° C. yields the alcohol of FormulaXXXIV.

Preparation of the 1,3,4-oxadiazole of Formula XXXVI is carried out asshown in Reaction Scheme 13 using methods well known to those skilled inthe art (ref: Joule, J. A.; Mills, K.; Smith, G. F. HeterocyclicChemistry, 3rd ed., Chapman & Hall: London, 1995; 452-456 and referencescited therein). For example, the ester of Formula XXXV is treated withhydrazine in methanol with heating up to the reflux point. The resultingacyl hydrazide intermediate is used without purification in a subsequentreaction with an alkyl acetimidate in pyridine with heating at reflux toprovide the oxadiazole of Formula XXXVI.

Synthesis of the 1,2,4-oxadiazole of Formula XXXVII is achieved as shownin Reaction Scheme 14 using methods well known to those skilled in theart (ref: Joule, J. A.; Mills, K.; Smith, G. F. Heterocyclic Chemistry,3rd ed., Chapman & Hall: London, 1995; 452-456 and references citedtherein). For example, treatment of the acid of Formula XVII withhydroxbenzotriazole, a carbodiimide, and acetamidoxime (N-hydroxyethanimidamide) in the presence of a base such as triethylamine providesan intermediate that is heated in refluxing pyridine to provide theoxadiazole of Formula XXXVII.

The 1,2,4-oxadiazole of Formula XXXIX is prepared from the nitrile ofFormula XXXVIII (Reaction Scheme 15) using methods well-known to thoseskilled in the art (ref: Joule, J. A.; Mills, K.; Smith, G. F.Heterocyclic Chemistry, 3rd ed., Chapman & Hall: London, 1995; 452-456and references cited therein). For example, reaction of the nitrile ofFormula XXXVIII with hydroxylamine in a solvent such as ethanol attemperatures up to reflux provides an intermediate N-hydroxyamidine thatis subsequently treated with acetyl chloride in the presence of a basesuch as triethylamine in a solvent such as CH₂Cl₂ to provide the1,2,4-oxadiazole of Formula XXXIX.

Reaction Scheme 16 shows the transformation of the amide of Formula XLto the ketone of Formula XLI. The amide of Formula XL, which is preparedas described in Reaction Scheme 6, is treated with a methylorganometallic reagent such as methyl magnesium bromide in a solventsuch as THF to provide the ketone of Formula XLI. The range of thereaction temperature is from −20° C. to 25° C.

β-Amino amides of Formula XLIII are prepared from acrylamides of FormulaXLII as shown in Reaction Scheme 17. For example, an acrylamide ofFormula XLII, which is prepared as described in Reaction Scheme 9, istreated with a primary or secondary amine in a solvent such as tolueneto provide the β-amino amide of Formula XLIII.

Preparation of the sulfonamide intermediate of Formula XLIX (a singleenantiomer of the compound of Formula III) is outlined in ReactionScheme 18. Reaction of the α-anion of the intermediate of Formula XLIV(ref: Josien, H.; Martin, A.; Chassaing, G. Tetrahedron Lett. 1991, 32,6547) with an alkylating agent such as an alkyl halide (e.g., an alkylchloride, alkyl bromide, or alkyl iodide) or an alkyl sulfonate (e.g.,an alkyl mesylate, alkyl tosylate, or alkyl trifluoromethanesulfonate)provides the intermediate of Formula XLV. The α-anion of the compound ofFormula XLIV is formed by treatment with a strong base such as an alkyllithium (e.g., n-BuLi) or a dialkylamide (e.g., lithiumdiisopropylamide) in a solvent such as THF with or without a co-solventsuch as HMPA. The reaction temperature is typically between −78° C. and25° C. Removal of the benzhydrylidene protecting group of the compoundof Formula XLV is carried out under conditions well known to thoseskilled in the art (ref.: T. W. Greene and P. G. M. Wuts, “ProtectingGroups in Organic Synthesis”, Wiley Interscience, New York, 1999, pp.587-588). For example, the compound of Formula XLV is treated with anacid such as HCl in water in a solvent such as THF to effect hydrolysisof the benzhydrylidene protecting group. The resulting amine of FormulaXLVI is treated with a sulfonylating agent as described for ReactionScheme 1 to provide the sulfonamide of Formula XLVII. Hydrolysis of theacylsulfonamide of Formula XLVII to afford the acid of Formula XLVIII iscarried out by treatment with hydroxide ion, for example in the form oflithium hydroxide, in the presence of additives such as lithium bromideand tetrabutylammonium bromide. The acid of Formula XLVIII is convertedto the amide of formula XLIX under conditions that are well known tothose skilled in the art (general ref for amide preparation.: R. C.Larock “Comprehensive Organic Transformations, VCH Publishers, New York,1989, pp. 972-976). For example, reaction of the compound of FormulaXLVIII with ammonium chloride in the presence of 1-hydroxybenzotriazole,a carbodiimide reagent, and an amine base such as diisopropylethylamineprovides the amide of Formula XLIX. This reaction is typically run in apolar solvent such as DMF and at a reaction temperature from 0° C. to40° C. The amide of Formula XLIX is converted to the compounds ofFormula I by the method described in Reaction Scheme 1.

Reaction Scheme 19 illustrates one method for synthesis of anα-substituted (N-sulfonamido)acetamide intermediate of Formula IIIstarting with an activated glycine derivative of Formula L. Reaction ofthe compound of Formula L (ref.: Haufe, G.; Laue, K. W.; Triller, M. U.;Takeuchi, Y.; Shibata, N. Tetrahedron 1998, 54, p. 5929-5938; Kroger,S.; Haufe, G. Amino Acids 1997, 12, p. 363-372) with an alkylating agentsuch as an alkyl halide (e.g., an alkyl chloride, alkyl bromide, oralkyl iodide) or an alkyl sulfonate (e.g., an alkyl mesylate, an alkyltosylate, or an alkyl trifluoromethanesulfonate) in the presence of abase such as potassium carbonate and an additive such astetrabutylammonium bromide and in an inert solvent such as acetonitrileat a reaction temperature of between 25° C. and 70° C. provides thecompound of Formula LI. Removal of the benzhydrylidene protecting groupis carried out under conditions well known to those skilled in the art(ref.: T. W. Greene and P. G. M. Wuts, “Protecting Groups in OrganicSynthesis”, Wiley Interscience, New York, 1999, pp. 587-588). Forexample, a solution of the compound of Formula LI in a solvent such asdiethyl ether is treated with aqueous acid (e.g., aqueous HCl),typically at a reaction temperature of between 0° C. and 30° C., toprovide the amine ester of Formula LII. Conversion of the ester ofFormula LII to the amide of Formula II is carried out using procedureswell known to those skilled in the art. For example, when the compoundof Formula LII is an ethyl ester, hydrolysis of the ester is achieved bytreatment of an ethereal solution with an acid such as HCl, typicallywith heating of the reaction mixture in refluxing solvent. The resultingacid intermediate is then converted to a methyl ester of Formula LII bytransformation to the acid chloride under standard conditions, (e.g.,treatment with thionyl chloride and methanol), followed by reaction withaqueous ammonia in a solvent such as toluene (ref.: R. C. Larock“Comprehensive Organic Transformations, VCH Publishers, New York, 1989,pp. 972-976). The amine of Formula II is converted to the compound ofFormula I as described in Reaction Scheme 1.

Preparation of the compound of Formula LVII is shown in Reaction Scheme20. Alkene LIII is prepared as described in Reaction Scheme 18 from anintermediate of Formula XLIV and 1-bromo-2-methyl-2-propene). Treatmentof the alkene of Formula LIII with HF. pyridine in a solvent such as THFat a reaction temperature between 0° C. and 25° C. affords thefluoroalkyl compound of Formula LIV. Conversion of the compound ofFormula LIV to the amide of Formula LV is accomplished as described inReaction Scheme 18. Transformation of the amide of Formula LV to thecompound of Formula LVI is carried out as described in Reaction SchemeI.

The syntheses of the compounds of Formula LXII and Formula LXIV areoutlined in Reaction Scheme 21. Ethyl 2-amino-4-methyl-4-pentenoate(prepared as in Reaction Scheme 19 from (benzhydrylideneamino)aceticacid ethyl ester and 1-bromo-2-methyl-2-propene) is treated with asulfonylating agent such as a sulfonyl chloride in the presence of abase such as tri ethyl amine in an inert solvent such as CH₂Cl₂ toafford the ester of Formula LVII. Reaction of the ester of Formula LVIIwith HF. pyridine in a solvent such as THF and at a reaction temperatureof between 0° C. and 25° C. provides a mixture of the fluoroalkylderivative of Formula LVIII and the lactone of Formula LIX. Theseproducts are separated and carried on individually into subsequentreactions.

The ester of Formula LVIII is hydrolyzed to the acid of Formula LX usingmethods well known to those skilled in the art (ref.: T. W. Greene andP. G. M. Wuts, “Protecting Groups in Organic Synthesis”, WileyInterscience, New York, 1999 pp. 373-442). For example, treatment of theester of Formula LVIII with aqueous sodium hydroxide in a solvent suchas methanol affords the acid of Formula LX. The acid of Formula LX isconverted to the amide of Formula LXI using the procedure described inReaction Scheme 18 for the preparation of the amide of Formula XLIX.Preparation of the amide of Formula LXII from the compound of FormulaLXI is achieved as described in Reaction Scheme 1.

For the lactone of Formula LIX, treatment with aqueous ammonia providesthe amide of Formula LXIII. This reaction is typically carried out withheating in a sealed tube. The reaction temperature is between 40° C. and80° C. Further conversion of the intermediate of Formula LXIII to thesulfonamide of Formula LXIV proceeded as described in Reaction Scheme 1.

The synthetic sequence for preparation of a difluoroalkyl amide ofFormula LXIX is shown in Reaction Scheme 22. The compound of Formula Lis treated with 4-bromo-1-butene in the presence of a base suchpotassium carbonate in the presence of a tetraalkylammonium halide saltsuch as tetrabutylammonium bromide in a solvent such as CH₃CN at atemperature from 20° C. to 70° C. Removal of the benzhydrylideneprotecting group as described in Reaction Scheme 19 provides anintermediate amine that is then treated with a sulfonylating reagentsuch as a sulfonyl chloride to provide the ester of Formula LXV.Alkylation of the sulfonamide nitrogen is accomplished using theprocedure described in Reaction Scheme 1 to afford the compound ofFormula LXVI. Conversion of the alkene of Formula LXVI to the aldehydeof Formula LXVII is achieved by reaction of the alkene with osmiumtetroxide and trimethylamine N-oxide in a solvent such as acetone,followed by treatment with sodium periodate. The reaction temperature istypically 20° C. to 40° C. Reaction of the aldehyde of Formula LXVIIwith a fluorinating agent such as DAST in a solvent such as CH₂Cl₂yields the difluoroalkyl derivative of Formula LXVIII. The compound ofFormula LXVIII is converted to the amide of Formula LXIX by hydrolysisof the ester to an acid using an base such as sodium hydroxide in asolvent such as methanol. The intermediate acid was converted to theamide using conditions well known to those skilled in the art (ref.: R.C. Larock “Comprehensive Organic Transformations, VCH Publishers, NewYork, 1989, pp. 972-976). For example, reaction of the acid withammonium chloride in the presence of hydroxybenzotriazole and acarbodiimide reagent and an amine base such as diusopropylethylamineprovided the amide of Formula LXIX. This reaction is typically run in apolar solvent such as DMF and at a reaction temperature from 0° C. to40° C.

The α-amino amide of Formula LXXI is prepared using the reaction showedin Reaction Scheme 23. The amide of Formula LXX is prepared as describedin Reaction Scheme 9. Treatment of the compound of Formula LXX with asecondary or tertiary amine in a solvent such as THF at a reactiontemperature between 20° C. and 40° C. affords the amine of Formula LXXI.

In a preferred embodiment, the present invention includes compounds ofFormula Ia or a pharmaceutically acceptable salt thereof

wherein:

-   R¹ is selected from the group consisting of    -   (a) a straight or branched-chain C₁₋₆ alkyl or C₂₋₆alkenyl        optionally substituted with substituents selected from the group        consisting of hydroxy, C₃₋₇ cycloalkyl, C₁₋₄alkoxy,        C₁₋₄alkylthio, and halogen;    -   (b) C₃₋₇ cycloalkyl optionally substituted with hydroxy or        halogen;-   R² is selected from the group consisting of    -   (a) a straight or branched-chain C₁₋₆alkyl or C₃₋₆alkenyl        optionally substituted with substituents selected from the group        consisting of halogen, C₁₋₄alkoxy, and NR⁴R⁵;    -   (b) C₃₋₇ cycloalkylmethyl optionally substituted with        substituents selected from the group consisting of amino,        (C₁₋₄alkyl)NH—, di(C₁₋₄alkyl)N—, C₁₋₄alkylC(═O)NH—, and        C₁₋₄alkylOC(═O)NH—;    -   (c) a straight or branched-chain C₁₋₆alkyl-C(═O)-A;    -   (d) —B-naphthyl;    -   (e)        -   D and E are each independently a direct bond, a straight or            branched-chain C₁₋₆alkyl, C₂₋₆ alkenyl, or C₃₋₇ cycloalkyl;        -   Z is selected from the group consisting of hydrogen,            C₁₋₄alkyl, C₁₋₄alkoxy, halogen, cyano, hydroxy, —OCHF₂,            —OCF₃, —CF₃, and —CHF₂;        -   X and Y are each independently selected from the group            consisting of hydrogen, hydroxy, halogen, (halogen)₃C—,            (halogen)₂CH—, C₁₋₄alkylS—, C₁₋₄alkylS(O)—, C₁₋₄alkylSO₂—,            nitro, F₃S—, and cyano;        -   —OR⁶;        -   —NR⁴R⁵;        -   —NR⁷C(═O)R⁸;        -   —NR⁷C(═O)OR⁸;        -   —N—HSO₂C₁₋₄alkyl;        -   —N(SO₂C₁₋₄alkyl)₂;        -   —C(═O)W wherein W is selected from the group consisting of            hydroxy, C₁₋₄alkyl, C₁₋₄alkoxy, phenoxy, and —NR⁴R⁵;        -   —OC(═O)C₁₋₄alkyl;        -   -phenyl in which said phenyl is optionally substituted with            cyano, halogen, C₁₋₄alkoxy, C₁₋₄alkylS—, CH₃C(═O),            C₁₋₄alkylS(O)—, or C₁₋₄alkylSO₂—; and        -   heterocyclic group, in which said heterocyclic group is            selected from the group consisting of furanyl, thiofuranyl,            pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl,            pyridinyl, pyrimidinyl, oxadiazolyl, oxazolyl, isoxazolyl,            thiadiazolyl, and thiazolyl, wherein said heterocyclic group            is optionally substituted with substituents selected from            the group consisting of cyano, halogen, C₁₋₄alkyl,            (halogen)C₁₋₄alkyl, and CO₂C₁₋₄alkyl;    -   (f) —B-(heterocycle), in which said heterocycle is selected from        the group consisting of furanyl, thiofuranyl, pyrrolyl,        imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl,        pyrimidinyl, oxadiazolyl, oxazolyl, isoxazolyl, thiadiazolyl and        thiazolyl wherein said heterocycle is optionally substituted        with substituents selected from the group consisting of cyano,        halogen, C₁₋₄alkyl, CO₂C₁₋₄alkyl, amino, (C₁₋₄alkyl)NH—,        di(C₁₋₄alkyl)N—, morpholin-4-yl, thiomorpholin-4-yl,        pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, and        4-(C₁₋₆alkyl)piperazin-1-yl;    -   (g) —B-(piperidin-4-yl), in which said piperidin-4-yl is        optionally substituted with substituents selected from the group        consisting of a straight or branched-chain C₁₋₆alkyl,        CH₂C(═O)phenyl, phenyl and phenylmethyl in which said C₁₋₆alkyl        and said phenyl are optionally substituted with substituents        selected from the group consisting of cyano, halogen,        benzimidazol-2-yl, pyridyl and tetrahydrofuran-2-yl; and        —C(═O)W′ wherein W′ is selected from the group consisting of        C₁₋₄alkoxy, R⁹, and —NR⁴R⁵;-   A is hydroxy, C₁₋₄alkoxy or NR⁴R⁵;-   B is a straight or branched-chain C₁₋₆alkyl or C₃₋₆alkenyl;-   R³ is phenyl or pyridyl optionally substituted with substituents    selected from the group consisting of halogen, hydroxy, C₁₋₄alkoxy,    C₁₋₄alkyl, (halogen)₃C—, (halogen)₂CH—, and halogenCH₂—;-   R⁴ and R⁵ each are independently hydrogen, a straight or    branched-chain C₁₋₆ alkyl, C₃₋₆ alkenyl, C₃₋₆ alkynyl, C₃₋₇    cycloalkyl, C₃₋₇ cycloalkylmethyl, C₁₋₄alkoxy, phenyl, benzyl,    pyridyl, piperidin-4-yl, indan-1-yl, indan-2-yl,    tetrahydrofuran-3-yl, or pyrrolidin-3-yl; in which each is    optionally substituted with substituents selected from the group    consisting of hydroxy, cyano, halogen, (halogen)₃C—, (halogen)₂CH—,    halogenCH₂—, hydroxymethyl, benzyloxymethyl, phenyl, pyridyl,    C₁₋₄alkyl, C₁₋₄alkoxy, (halogen)₃C—O—, (halogen)₂CH—O—,    C₁₋₄alkylthio, amino, (C₁₋₄alkyl)NH—, di(C₁₋₄alkyl)N—,    morpholin-4-yl, thiomorpholin-4-yl, pyrrolidin-1-yl, piperidin-1-yl,    piperazin-1-yl, 4-(C₁₋₆alkyl)piperazin-1-yl, 4-phenylpiperazin-1-yl,    4-benzylpiperazin-1-yl, 4-pyridylpiperazin-1-yl, CO₂H, CO₂C₁₋₄alkyl,    C(═O)NHC₁₋₄alkyl, and C(═O)N(C₁₋₄alkyl)₂;-   R⁴ and R⁵ taken together may be morpholin-4-yl, thiomorpholin-4-yl,    pyrrolidin-1-yl, 1,2,3,4-tetrahydroisoquinolin-2-yl,    decahydroquinolin-1-yl, piperidin-1-yl, piperazin-1-yl,    [1,4]-oxazepan-4-yl, azetidin-1-yl, 2,3-dihydro-1H-isoindol-2-yl, or    2,3-dihydro-1H-indol-1-yl; in which each is optionally substituted    with substituents selected from the group consisting of hydroxy,    cyano, halogen, (halogen)₃C—, (halogen)₂CH—, halogenCH₂—, phenyl,    pyridyl, benzyl, C₁₋₆alkyl, C₃₋₇ cycloalkyl, C₁₋₄alkoxy,    C₁₋₄alkylthio, amino, (C₁₋₄alkyl)NH—, di(C₁₋₄alkyl)N—, CO₂H,    CO₂C₁₋₄alkyl, C(—O)NHC₁₋₄alkyl, and C(═O)N(C₁₋₄alkyl)₂;-   R⁶ is a straight or branched-chain C₁₋₆alkyl, C₃₋₆ alkenyl, benzyl,    or phenyl in which each is optionally substituted with substituents    selected from the group consisting of halogen, C₁₋₄alkyl,    C₁₋₄alkoxy, amino, (C₁₋₄alkyl)NH—, di(C₁₋₄alkyl)N—,    (C₁₋₄alkyl)(phenyl)N—, morpholin-4-yl, thiomorpholin-4-yl,    pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, and    4-(C₁₋₆alkyl)piperazin-1-yl;-   R⁷ is hydrogen, a straight or branched-chain C₁₋₆ alkyl;-   R⁸ is a straight or branched-chain C₁₋₆alkyl, C₃₋₇ cycloalkyl,    phenyl, pyridyl, or furanyl; in which each is optionally substituted    with substituents selected from the group consisting of halogen,    C₁₋₄alkyl, C₁₋₄alkoxy, (C₁₋₄alkyl)NH—, di(C₁₋₄alkyl)N—,    morpholin-4-yl, thiomorpholin-4-yl, pyrrolidin-1-yl, piperidin-1-yl,    piperazin-1-yl, and 4-(C₁₋₆alkyl)piperazin-1-yl;-   R⁹ is a straight or branched-chain C₁₋₆alkyl, C₃₋₆ alkenyl, benzyl,    phenyl, oxazolyl or pyridyl; in which each is optionally substituted    with substituents selected from the group consisting of halogen,    (halogen)₃C—, (halogen)₂CH—, halogenCH₂—, C₁₋₄alkyl, C₁₋₄alkoxy,    amino, (C₁₋₄alkyl)NH—, di(C₁₋₄alkyl)N—, morpholin-4-yl,    thiomorpholin-4-yl, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl,    and 4-(C₁₋₆alkyl)piperazin-1-yl;    or a non-toxic pharmaceutically acceptable salt thereof.

In another preferred embodiment, the invention includes compounds ofFormula Ia or a pharmaceutically acceptable salt thereof wherein R³ isphenyl optionally substituted with substituents selected from the groupconsisting of halogen, hydroxy, C₁₋₄alkoxy, C₁₋₄alkyl, (halogen)₃C—,(halogen)₂CH—, and halogenCH₂—.

In yet another preferred embodiment, the invention includes compounds ofFormula Ia or a pharmaceutically acceptable salt thereof wherein R² is

Biological Testing Methods

Compounds of Formula (I) are expected to possess γ-secretase inhibitoryactivity. The detection of γ-secretase activity requires assays capableof reliable, accurate and expedient detection of γ-secretase cleavageproducts, particularly Aβ. The γ-secretase inhibitory activity of thecompounds of the present invention is demonstrated using assays for suchactivity, for example, using the assays described below. Compoundswithin the scope of the present invention have been shown to inhibit theactivity of γ-secretase, as determined using assays for such activity.

Compounds provided by this invention should also be useful as standardsand reagents in determining the ability of a potential pharmaceutical toinhibit Aβ production. These would be provided in commercial kitscomprising a compound of this invention.

In Vitro Binding Assay to Identify γ-Secretase Inhibitors.

Competitive binding assays can be used to identify molecules thatinhibit the binding of a radiolabeled γ-secretase inhibitor andtherefore inhibit γ-secretase activity. For example, [³H]-Compound A canbe used for binding assays with membranes from THP-1 cells (Seiffert,D.; Bradley, J. et al., J. Biol. Chem. 2000, 275, 34086-34091). CompoundA is (2R,3S)N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide,the synthesis of which is described in U.S. Pat. No. 6,331,408 (Dec. 18,2001); PCT Publication WO 00/28331; PCT Publication WO 00/07995; andSeiffert, D., Bradley, J. et al., J. Biol. Chem. 2000, 275. 34086-34091.

For these assays, THP-1 cells were grown in spinner cultures in RPMI1640 containing L-glutamine and 10 μM β-mercaptoethanol to a density of5×10⁵ cells/ml. Cells were harvested by centrifugation and cell pelletswere quick frozen in dry ice/ethanol and stored at −70° C. prior to use.The pellets of approximately 2×10⁴ THP-1 cells were homogenized using aBrinkman Polytron at setting 6 for 10 sec. The homogenate wascentrifuged at 48,000×g for 12 min, and the resulting pellet was washedby repeating the homogenization centrifugation. The final cell pelletwas resuspended in buffer to yield a protein concentration ofapproximately 0.5 mg/ml. Assays were initiated by the addition of 150 μlof membrane suspension to 150 μl of assay buffer containing 0.064 μCi ofradioligand and various concentrations of unlabeled compounds. Bindingassays were performed in duplicate in polypropylene 96-well plates in afinal volume of 0.3 ml containing 50 mM Hepes, pH 7.0, and 5% dimethylsulfoxide. Nonspecific binding was defined using incubations with 300 nMcompound A (Seiffert, D., Bradley, J. et al., J. Biol. Chem. 2000, 275,34086-34091). After incubating at 23° C. for 1.3 hr, bound ligand wasseparated from free radioligand by filtration over GFF glass fiberfilters presoaked in 0.3% ethyleneimine polymer solution. Filters werewashed three times with 0.3 ml of ice cold phosphate-buffered saline, pH7.0, containing 0.1% Triton X-100. Filter-bound radioactivity wasmeasured by scintillation counting. IC₅₀ values were then determined andused to calculate K_(i) values using the Cheng-Prusoft correction forIC₅₀ values. Compounds were scored as active γ-secretase inhibitors ifK_(i) values were less than 10 μM.

Examples of the results obtained when the invention compounds aresubjected to the above described assay are shown in Table 1. In thetable, an inhibitory concentration (IC₅₀) of less than or equal to 50 nMis represented by +++; between 50 nM and 500 nM by ++; between 500 nMand 10000 nM by +. TABLE 1 Examples of activity in the in vitro bindingAssay EXAMPLE ACTIVITY RATING^(a) 96 +++ 123 +++ 159 +++ 315 ++ 341 ++357 ++ 362 +++ 365 +++ 366 +++ 367 + 376 ++ 379 +++ 385 +++ 389 +++ 394+++ 403 ++ 405 +++ 408 + 409 ++ 437 +++ 441 +++ 443 ++ 445 +++ 447 +++450 ++ 451 + 452 ++ 457 ++ 464 + 474 +++ 476 +++ 479 ++ 486 +++^(a)Activity based on IC₅₀ values:+++ = <50 nM++ = 50-500 nM+ = >500 nM and <10,000 nMIn Vitro Assay to Identify γ-Secretase Inhibitor Based on the Inhibitionof Aβ Formation from Membrane Preparations.

An isolated membrane fraction which contains functionally activeγ-secretase and β-APP substrates can generate γ-secretase cleavageproducts including Aβ (Roberts, S. B.; Hendrick, J. P.; Vinitsky, A.;Lewis, M.; Smith, D. W.; Pak, R. PCT Publication WO 01/0175435;Fechteler, K.; Kostka, M.; Fuchs, M. Patent Application No. DE99-19941039; Shearman, M.; Beher, D. et al., Biochemistry, 2000, 39,8698-8704; Zhang, L. Song, L. et al., Biochemistry 2001, 40, 5049-5055).An isolated membrane fraction can be prepared from human derived celllines such as HeLa and H4 which have been transfected with wild type ormutant forms of β-APP or a human alkaline phosphatase β-APP fusionconstruct, and stably express high levels of γ-secretase substrates. Theendogenous γ-secretase present in the isolated membranes prepared at0-4° C. cleaves the β-APP substrates when the membranes are shifted from0-4 to 37° C. Detection of the cleavage products including Aβ can bemonitored by standard techniques such as immunoprecipitation (Citron,M.; Diehl, T. S. et al., Proc. Natl. Acad. Sci. USA, 1996, 93,13170-13175), western blot (Klafki, H.-W.; Ambramowski, D. et al., J.Biol. Chem. 1996, 271, 28655-28659), enzyme linked immunosorbent assay(ELISA) as demonstrated by Seubert, P.; Vigo-Pelfrey, C. et al., Nature,1992, 359, 325-327, or by a preferred method using time-resolvedfluorescence of the homogeneous sample containing membranes and Aβ(Roberts, S. B.; Hendrick, J. P.; Vinitsky, A.; Lewis, M.; Smith, D. W.;Pak, R. PCT Publication WO 01/0175435; Shearman, M.; Beher, D. et al.,Biochemistry, 2000, 39, 8698-8704). The Aβ present in a homogeneoussample containing membranes can be detected by time-resolvedfluorescence with two antibodies that recognize different epitopes ofAβ. One of the antibodies recognizes an epitope that is present in Aβbut not present in the precursor fragments; preferably the antibodybinds the carboxyl terminus of Aβ generated by the γ-secretase cleavage.The second antibody binds to any other epitope present on Aβ. Forexample, antibodies that bind the N-terminal region (e.g., 26D6-B2-B3®SIBIA Neurosciences, La Jolla, Calif.) or bind the C-terminal end (e.g.,9S3.2® antibody, Biosolutions, Newark, Del.) of the Aβ peptide areknown. The antibodies are labeled with a pair of fluorescent adductsthat transfer fluorescent energy when the adducts are brought in closeproximity as a result of binding to the N- and C-terminal ends orregions of Aβ. A lack of fluorescence is indicative of the absence ofcleavage products, resulting from inhibition of γ-secretase. Theisolated membrane assay can be used to identify candidate agents thatinhibit the activity of γ-secretase cleavage and Aβ production.

A typical membrane-based assay requires 45 μg membrane protein per wellin a 96- or 384-well format. Membranes in a neutral buffer are combinedwith the test compound and shifted from 0-4 to 37° C. Test agents maytypically consist of synthetic compounds, secondary metabolites frombacterial or fungal fermentation extracts, or extracts from plant ormarine samples. All synthetic agents are initially screened at dosesranging from 10-100 μM or in the case of extracts at sufficient dilutionto minimize cytotoxicity. Incubation of the membranes with the testagent will continue for approximately 90 minutes at which timefluorescence labeled antibodies are added to each well for Aβquantitation. The time-resolved fluorescence detection and quantitationof Aβ is described elsewhere (Roberts, S. B.; Hendrick, J. P.; Vinitsky,A.; Lewis, M.; Smith, D. W.; Pak, R. PCT Publication WO 01/0175435;Shearman, M.; Beher, D. et al., Biochemistry, 2000. 39, 8698-8704).Results are obtained by analysis of the plate in a fluorescence platereader and comparison to the mock treated membranes and samples in whichknown amounts of Aβ were added to construct a standard concentrationcurve. A positive acting compound is one that inhibits the Aβ relativeto the control sample by at least 50% at the initial testedconcentration. If a compound is found to be active then a dose responseexperiment is preformed to determine the lowest dose of compoundnecessary to elicit the inhibition of the production of Aβ. Compoundswere scored as active γ-secretase inhibitors if K_(i) values were lessthan 10 μM.

Examples of the results obtained when the invention compounds aresubjected to the above described assay are shown in Table 2. In thetable, an inhibitory concentration (IC₅₀) of less than or equal to 50 nMis represented by +++; between 50 nM and 500 nM by ++; between 500 nMand 10000 nM by +. TABLE 2 Examples of activity in the in vitro assaybased on the inhibition of Aβ formation from membrane preparationsEXAMPLE ACTIVITY RATING^(a) 1 +++ 2 +++ 3 +++ 4 +++ 5 +++ 6 +++ 7 +++ 8+++ 9 +++ 10 +++ 11 +++ 12 +++ 13 +++ 14 +++ 15 +++ 16 +++ 17 +++ 18 ++19 ++ 20 ++ 21 +++ 22 +++ 23 +++ 24 +++ 25 +++ 26 +++ 27 ++ 28 ++ 29 +++30 ++ 31 ++ 32 +++ 33 +++ 34 +++ 35 ++ 36 ++ 37 +++ 38 +++ 39 +++ 40 +++41 +++ 42 +++ 43 +++ 44 +++ 45 +++ 46 +++ 47 +++ 48 +++ 49 ++ 50 +++ 51+++ 52 +++ 59 ++ 61 +++ 83 + 85 + 87 +++ 89 +++ 95 +++ 103 +++ 113 ++122 + 133 +++ 153 ++^(a)Activity based on IC₅₀ values:+++ = <50 nM++ = 50-500nM+ = >500 nM and <10,000 nMIn Vitro Assays to Identify γ-Secretase Inhibitor Based on theInhibition of Aβ Formation in Cultured Cells.

Cultured human cell lines, such as HEK293 and H4 cells, which expressAPP and γ-secretase activity or transfected derivative cell lines thatoverexpress wild-type APP, mutant APP, or APP fusion proteins willsecrete Aβ peptides into the culture media that can be quantified aspreviously outlined (Dovey, H., John, V. et al., J. Neurochem. 2001, 76,173-181). The incubation of these cultured cells with γ-secretaseinhibitors decreases the production of Aβ peptides. For instance, H4cells stably transfected to overexpress the HPLAP-APP fusion proteindescribed above were grown as above, detached, and adjusted to 2×10⁵cells/ml. 100 μl of the resulting suspension was then added to each wellof a 96-well plate. After 4 hrs, the media was removed and replaced with100 μl serum-free media containing various dilutions of the testcompound. Plates were then incubated for 18 hrs at 37° C. and a 100 μlaliquot of the tissue culture supernatant was removed for determinationof Aβ levels using time-resolved fluorescence of the homogenous sampleas outlined above. Alternately, the other methods described above for Aβdetermination could be used. The extent of Aβ inhibition was used tocalculate the IC₅₀ value for the test compound. Compounds of the presentinvention are considered active when tested in the above assay if theIC₅₀ value for the test compound is less than 50 μM.

Examples of the results obtained when the invention compounds aresubjected to the above described assay are shown in Table 3. In thetable, an inhibitory concentration (IC₅₀) of less than or equal to 50 μMis represented by +++; between 50 nM and 500 nM by ++; between 500 nMand 50000 nM by +. TABLE 3 Examples of activity in the in vitro assaybased on the inhibition of Aβ formation in cultured cells EXAMPLEACTIVITY RATING^(a) 1 +++ 5 +++ 19 ++ 26 +++ 38 +++ 41 +++ 51 +++ 55 +++61 +++ 72 +++ 80 +++ 89 +++ 96 +++ 101 +++ 123 +++ 127 ++ 143 +++ 147 ++158 +++ 171 ++ 193 +++ 203 +++ 205 ++ 207 +++ 245 +++ 246 +++ 249 ++ 254+++ 256 +++ 260 +++ 272 +++ 280 ++ 282 +++ 288 ++ 301 ++ 302 +++ 321 ++322 +++ 329 +++ 330 ++ 331 + 340 +++ 341 ++ 342 +++ 349 +++ 352 ++ 358++ 359 +++ 366 +++ 367 + 378 +++ 383 +++ 394 +++ 403 ++ 416 +++ 418 +++424 +++ 433 +++ 434 +++ 439 +++ 442 +++ 472 +++ 481 + 492 ++ 495 +++ 497+++^(a)Activity based on IC₅₀ values:+++ = <50 nM++ = 50-500 nM+ = >500 nM and <10,000 nM

Compounds of the present invention have been demonstrated to have anIC₅₀ value less than 10 μM in one or all of the above assays. Therefore,the compounds of Formula I or pharmaceutical compositions thereof areuseful in the treatment, alleviation or elimination of disorders orother disorders associated with the inhibition of β-amyloid peptide.

In addition to cleaving APP, γ-secretase cleaves other substrates,including: the Notch family of transmembrane receptors (reviewed in:Selkoe, D. Physiol. Rev. 2001, 81, 741-766; Wolfe, M. J. Med. Chem. 200144, 2039-2060); LDL receptor-related protein (May, P., Reddy, Y. K.,Herz, J. J. Biol. Chem. 2002, 277, 18736-18743); ErbB-4 (Ni, C. Y.,Murphy, M. P., Golde, T. E., Carpenter, G. Science 2001, 294,2179-2181); E-cadherin (Marambaud, P., Shioi, J., et al., EMBO J. 2002,21, 1948-1956); and CD44 (Okamoto, I., Kawano, Y., et al., J. Cell Biol.2001, 155, 755-762). If inhibition of cleavage of non-APP substratescauses undesirable effects in humans, then desired γ-secretaseinhibitors would preferentially inhibit APP cleavage relative tounwanted substrates. Notch cleavage can be monitored directly bymeasuring the amount of cleavage product or indirectly by measuring theeffect of the cleavage product on transcription (Mizutani, T.,Taniguchi, Y., et al. Proc. Natl. Acad. Sci. USA 2001, 98, 9026-9031).

In Vivo Assays for the Determination of Aβ Reduction by γ-SecretaseInhibitors.

In vivo assays are available to demonstrate the inhibition ofγ-secretase activity. In these assays, animals, such as mice, thatexpress normal levels of APP and γ-secretase or are engineered toexpress higher levels of APP and hence Aβ can be used to demonstrate theutility of γ-secretase inhibitors (Dovey, H., John, V., et al., J.Neurochem. 2001, 76, 173-181). In these assays, γ-secretase inhibitorswere administered to animals and Aβ levels in multiple compartments,such as plasma, cerebral spinal fluid, and brain extracts, weremonitored for Aβ levels using methods previously outlined. For instance,Tg2576 mice, which overexpress human APP, was administered γ-secretaseinhibitors by oral gavage at doses that will cause measurable Aβlowering, typically less than 100 mg/kg. Three hours after dosingplasma, brain, and CSF were collected, frozen in liquid nitrogen, andstored at −80° C. until analysis. For Aβ detection, plasma was diluted15-fold in PBS with 0.1% Chaps while CSF was diluted 15-fold in 1% Chapswith protease inhibitors (5 μg/ml leupeptin, 30 μg/ml aprotinin, 1 mMphenylmethylsulfonylfluoride, 1 μM pepstatin). Brains were homogenizedin 1% Chaps with protease inhibitors using 24 ml solution/g braintissue. Homogenates were then centrifuged at 100,000×g for 1 hr at 4° C.The resulting supernatants were then diluted 10-fold in 1% Chaps withprotease inhibitors. Aβ levels in the plasma, CSF, and brain lysate weremeasured using time-resolved fluorescence of the homogenous sample orone of the other methods previously described.

A γ-secretase inhibitor is considered active in one of the above in vivoassays if it reduces Aβ by at least 50% at a dosage of 100 mg/kg.

Therefore, the compounds of Formula I or pharmaceutical compositionsthereof are useful in the treatment, alleviation or elimination ofdisorders or other disorders associated with the inhibition of β-amyloidpeptide.

In another embodiment, this invention includes pharmaceuticalcompositions comprising at least one compound of Formula I incombination with a pharmaceutical adjuvant, carrier or diluent.

In still another embodiment, this invention relates to a method oftreatment or prevention of disorders responsive to the inhibition ofβ-amyloid peptide in a mammal in need thereof, which comprisesadministering to said mammal a therapeutically effective amount of acompound of Formula I or a nontoxic pharmaceutically acceptable salt,solvate or hydrate thereof.

In yet another embodiment, this invention relates to a method fortreating Alzheimer's Disease and Down's Syndrome in a mammal in needthereof, which comprises administering to said mammal a therapeuticallyeffective amount of a compound of Formula I or a non-toxicpharmaceutically acceptable salt, solvate or hydrate thereof.

For therapeutic use, the pharmacologically active compounds of Formula Iwill normally be administered as a pharmaceutical composition comprisingas the (or an) essential active ingredient at least one such compound inassociation with a solid or liquid pharmaceutically acceptable carrierand, optionally, with pharmaceutically acceptable adjuvants andexcipients employing standard and conventional techniques.

The pharmaceutical compositions include suitable dosage forms for oral,parenteral (including subcutaneous, intramuscular, intradermal andintravenous) bronchial or nasal administration. Thus, if a solid carrieris used, the preparation may be tableted, placed in a hard gelatincapsule in powder or pellet form, or in the form of a troche or lozenge.The solid carrier may contain conventional excipients such as bindingagents, fillers, tableting lubricants, disintegrants, wetting agents andthe like. The tablet may, if desired, be film coated by conventionaltechniques. If a liquid carrier is employed, the preparation may be inthe form of a syrup, emulsion, soft gelatin capsule, sterile vehicle forinjection, an aqueous or non-aqueous liquid suspension, or may be a dryproduct for reconstitution with water or other suitable vehicle beforeuse. Liquid preparations may contain conventional additives such assuspending agents, emulsifying agents, wetting agents, non-aqueousvehicle (including edible oils), preservatives, as well as flavoringand/or coloring agents. For parenteral administration, a vehiclenormally will comprise sterile water, at least in large part, althoughsaline solutions, glucose solutions and like may be utilized. Injectablesuspensions also may be used, in which case conventional suspendingagents may be employed. Conventional preservatives, buffering agents andthe like also may be added to the parenteral dosage forms. Thepharmaceutical compositions are prepared by conventional techniquesappropriate to the desired preparation containing appropriate amounts ofthe active ingredient, that is, the compound of Formula I according tothe invention. See, for example, Remington's Pharmaceutical Sciences,Mack Publishing Company, Easton, Pa., 17th edition, 1985.

The dosage of the compounds of Formula I to achieve a therapeutic effectwill depend not only on such factors as the age, weight and sex of thepatient and mode of administration, but also on the degree of β-APinhibition desired and the potency of the particular compound beingutilized for the particular disorder of disease concerned. It is alsocontemplated that the treatment and dosage of the particular compoundmay be administered in unit dosage form and that the unit dosage formwould be adjusted accordingly by one skilled in the art to reflect therelative level of activity. The decision as to the particular dosage tobe employed (and the number of times to be administered per day) iswithin the discretion of the physician, and may be varied by titrationof the dosage to the particular circumstances of this invention toproduce the desired therapeutic effect.

A suitable dose of a compound of Formula I or pharmaceutical compositionthereof for a mammal, including man, suffering from, or likely to sufferfrom any condition related to β-AP production as described herein,generally the daily dose will be from about 0.05 mg/kg to about 10 mg/kgand preferably, about 0.1 to 2 mg/kg when administered parenterally. Fororal administration, the dose may be in the range from about 1 to about75 mg/kg and preferably from 0.1 to 10 mg/kg body weight. The activeingredient will preferably be administered in equal doses from one tofour times a day. However, usually a small dosage is administered, andthe dosage is gradually increased until the optimal dosage for the hostunder treatment is determined. In accordance with good clinicalpractice, it is preferred to administer the instant compounds at aconcentration level that will produce an effective anti-amyloid effectwithout causing any harmful or untoward side effects. However, it willbe understood that the amount of the compound actually administered willbe determined by a physician, in the light of the relevant circumstancesincluding the condition to be treated, the choice of compound of beadministered, the chosen route of administration, the age, weight, andresponse of the individual patient, and the severity of the patient'ssymptoms.

The following examples are given by way of illustration and are not tobe construed as limiting the invention in any way inasmuch as manyvariations of the invention are possible within the spirit of theinvention.

DESCRIPTION OF THE SPECIFIC EMBODIMENTS

In the following examples, all temperatures are given in degreesCentigrade. Melting points were recorded on a Thomas Scientific Unimeltcapillary melting point apparatus and are uncorrected. Proton magneticresonance (¹H NMR) spectra were recorded on a Bruker Avance 300, aBruker Avance 400, or a Bruker Avance 500 spectrometer. All spectra weredetermined in the solvents indicated and chemical shifts are reported inδ units downfield from the internal standard tetramethylsilane (TMS) andinterproton coupling constants are reported in Hertz (Hz). Splittingpatterns are designated as follows: s, singlet; d, doublet; t, triplet;q, quartet; in, multiplet; br, broad peak; dd, doublet of doublet; br d,broad doublet; dt, doublet of triplet; hr s, broad singlet; dq, doubletof quartet. Infrared (IR) spectra using potassium bromide (KBr) orsodium chloride film were determined on a Jasco FT/IR-410 or a PerkinElmer 2000 FT-IR spectrometer from 4000 cm⁻¹ to 400 cm⁻¹, calibrated to1601 cm⁻¹ absorption of a polystyrene film and reported in reciprocalcentimeters (cm⁻¹). Optical rotations [α]_(D) were determined on aRudolph Scientific Autopol IV polarimeter in the solvents indicated;concentrations are given in mg/mL. Low resolution mass spectra (MS) andthe apparent molecular (MH⁺) or (M−H)⁺ was determined on a FinneganSSQ7000. High resolution mass spectra were determined on a FinneganMAT900. Liquid chromatography (LC)/mass spectra were run on a ShimadzuLC coupled to a Water Micromass ZQ.

The following abbreviations are used: DMF (dimethylformamide); THF(tetrahydrofuran); DMSO (dimethylsulfoxide), Leu (leucine); TFA(trifluoroacetic acid); DAST [(diethylamino)sulfur trifluoride], HPLC(high pressure liquid chromatography); rt (room temperature); aq.(aqueous).Exemplification of Reaction Scheme 1

(2R)-2-(4-Chlorobenzenesulfonylamino)-4-nmethylpentanoic acid amide

To a solution of (D)-leucinamide hydrochloride (0.25 g, 1.5 mmol), andEt₃N (0.43 mL, 3.0 mmol) in CH₂Cl₂ (150 mL) was added4-chlorobenzenesulfonyl chloride (380 mg, 1.8 mmol). The resultingsolution was stirred at rt for 18 h. The reaction was then diluted withCH₂Cl₂ (200 mL) and washed with H₂O, 0.5 N HCl, brine, and dried overMgSO₄, to afford the titled compound (410 mg) as a white solid in 90%yield. MS (ESI), (M+H)⁺ 305.2; ¹H NMR (DMSO-d₆) δ 7.77 (d, 2H, J=8.7),7.62 (d, 2H, J=8.7), 6.90 (br s, 1H), 3.67 (m, 1H), 1.54 (m, 1H), 1.31(m, 2H), 0.81 (d, 3H, J=7.0), 0.71 (d, 3H, J=7.0).Method A for Conversion of III to I:

(2R)-2-[N-(4-Chlorobenzenesulfonyl)-N-(4-methoxybenzyl)amino]-4-methylpentanoicacid amide (Example 1)

(2R)-2-(4-Chlorobenzenesulfonylamino)-4-methylpentanoic acid amide (300mg, 1 mmol), K₂CO₃ (170 mg, 1.2 mmol), and 4-methoxybenzyl chloride (170mg, 1.1 mmol) in DMF (25 mL) was heated to 60° C. for 18 h. The reactionwas then diluted with EtOAc (150 mL) and washed with H₂O, brine, driedover MgSO₄ and concentrated to give a crude white wax. Furtherpurification by flash chromatography (SiO₂, 25% EtOAc/hexanes) affordedthe titled compound (297 mg) as a white solid in 70% yield.[α]_(D)=+44.2 (c 1.00, MeOH); MS (ESI), (M−H)⁻ 422.9; ¹H NMR (CDCl₃) δ7.63 (d, 2H, J=7.0), 7.42 (d, 2H, J=7.0), 7.25 (d, 2H, J=8.0), 6.79 (d,2H, J=8.0), 6.25 (br s, 1H), 5.35 (br s, 1H), 4.36 (dd, 2H, J=50, 15),4-26 (t, 1H, J=7.2), 3.78 (s, 3H), 1.83 (m, 1H), 1.18-1.34 (m, 2H), 0.75(d, 3H, J=7.0), 0.67 (d, 3H, J=7.0); IR (KBr) 3480, 2959, 1693, 1674,1514, 1333, 1158 cm⁻¹.Method B for Conversion of III to I:

Methyl 6-dimethylaminonicotinate

A solution of methyl 6-chloronicotinate (4.0 g, 23 mmol) indimethylamine/MeOH (2 M, 80 mL, 160 mmol) in a pressure vessel wasstirred at 95° C. for 2 h, cooled to rt and concentrated. The residuewas dissolved in EtOAc (250 mL), washed with water (2×150 mL), driedover Na₂SO₄, and concentrated to afford the title compound as a tansolid (4.1 g, 98%). MS (ESI), (M+H)⁺ 181.24; ¹H NMR (CDCl₃) δ 8.79 (s,1H), 7.99 (d, 1H, J=9.2), 6.45 (d, 1H, J=9.2), 3.85 (s, 3H), 3.15 (s,6H).

2-Dimethylamino-5-hydroxymethylpyridine

A solution of methyl 6-dimethylamino-nicotinate (4.14 g, 23.0 mmol) inanhydrous ether (80 mL) at 0° C. was treated with lithium aluminumhydride (1 M in ether, 20 mL, 20 mmol). The mixture was stirred at rtfor 0.5 h, cooled again to 0° C. and quenched slowly with sat. aq.NaHCO₃ (10 mL). The resulting mixture was stirred at rt for 0.5 h,filtered, and washed with ether. The combined filtrates were dried overNa₂SO₄ and concentrated to give the title compound as a beige waxy solid(3.5 g, 100%). MS (EST), (M+H)⁺ 153.4; ¹H NMR (CDCl₃) δ 8.06 (d, 1H,J=2.4), 7.47 (dd, 1H, J=2.4, 8.8), 6.45 (d, 1H, J=8.8), 4.50 (s, 2H),3.06 (s, 6H), 1.98 (br s, 1H).

(2R)-2-[N-(4—Chlorobenzenesulfonyl)-N-(2-dimethylaminopyridin-5-yl)amino]-4-fluoro-4-methylpentanoicacid amide TFA salt (Example 459)

To a cloudy solution of(2R)-2-[(4-chlorobenzenesulfonylamino)-4-fluoro-4-methylpentanoic acidamide (prepared as in Reaction Scheme 20 or from γ-fluoro-D-Leu-OHmethyl ester, Papageorgiou et. al., Bioorg. & Med. Chem. Lett. 1994,Vol. 4, p.p. 267-272; 0.060 g, 0.18 mmol),2-dimethylamino-5-hydroxymethylpyridine (71 mg, 0.46 mmol),triphenylphosphine (122 mg, 0.464 mmol) in CH₂Cl₂ (9.5 mL) at rt wasadded dropwise diisopropyl azodicarboxylate (75 μL, 0.46 mmol). Theresulting pale yellow solution was stirred at rt for 2 h andconcentrated under vacuum. The residue was dissolved in methanol anpurified by reverse phase preparative HPLC (YMC S5, ODS, MeOH-water-TFA)to afford the title compound as a white foam (90 mg, 85%). MS (ESI),(M+H)⁺ 457.2; ¹H NMR (CDCl₃) δ 8.11 (s, 1H), 7.95 (d, 1H, J=9.6), 7.77(d, 2H, J=6.8), 7.51 (d, 2H, J=6.8), 6.76 (d, 2H, J=9.6), 6.34 (s, 1H),6.02 (s, 1H), 4.58 (br d, 1H, J=8.4), 4.46 (d, 1H, J=16.0), 4.06 (d, 1H,J=16), 3.29 (s, 6H), 2.50 (m, 1H), 1.39 (m, 1H), 1.25 (d, 3H=22.0), 1.17(d, 3H, J=22.0).Exemplification of Reaction Scheme 1—Solid Support

Polymer-bound D-Leu-NH₂: FMOC-protected Rink amide resin (30 g, 0.61mmol/g, 18 mmol) was treated with piperidine/DMF solution (250 mL). Themixture was shaken at rt for 24 h, drained, washed with DMF (5×200 mL),CH₂Cl₂ (5×200 mL) and dried under vacuum. The resin was then treatedwith FMOC-D-Leu-OH (22 g, 62 mmol), 1-hydroxybenzotriazole hydrate (2.5g, 18 mmol), 1,3-diisopropylcarbodiimide (9.8 mL, 62 mmol), and DMF (250mL). The mixture was shaken for 20 h, drained, washed with DMF (4×200mL), DMF-water (1:1, 3×200 mL), DMF (3×200 mL), MeOH (3×200 mL), CH₂Cl₂(3×200 mL) and dried. The completion of reaction and the loading of theresin-bound FMOC-D-Leu-NH₂ (0.56 mmol/g) were determined by thetreatment of 52 mg of the resin with 10% (v/v) TFA/CH₂Cl₂ (2 mL) to give11 mg of FMOC-D-Leu-NH₂. The resin-bound FMOC-D-Leu-NH₂ was deprotectedwith 20% (v/v) piperidine/DMF solution (250 mL) to give polymer-boundD-Leu-NH₂ (20 g).

Polymer-bound (R)-2-(4-Chlorobenzenesulfonylamino)-4-methylpentanoicacid amide

The above polymer-bound D-Leu-NH₂ (20 g) was treated with CH₂Cl₂ (150mL), pyridine (100 mL) and 4-chlorophenylsulfonyl chloride (20.0 g, 94.8mmol). The mixture was shaken for 24 h, drained, washed with DMF (4×200mL), CH₂Cl₂ (4×200 mL) and concentrated to give polymer-bound(R)-2-(4-chlorobenzenesulfonylamino)-4-methylpentanoic acid amide as ayellow resin (22 g). The completion of the reaction and the loading ofthe resin (0.57 mmol/g) were determined by the treatment of 50 mg of theresin with 10% (v/v) TFA/CH₂Cl₂ (2 mL) to give 8.7 mg of(R)-2-(4-chlorobenzenesulfonylamino)-4-methylpentanoic acid amide.

(2R)-2-[N-(4-Chlorobenzenesulfonyl)-N-(4-methylbenzyl)amino]-4-methylpentanoicacid amide (Example 60)

To a mixture of polymer-bound(2R)-2-[N-(4-chlorobenzenesulfonyl)amino]-4-methylpentanoic acid amide(loading 0.45 mmol/g, 50.0 mg, 0.0225 mmol), 4-methylbenzyl bromide (44mg, 0.24 mmol) and DMF (1.5 mL) was added2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diaza-phosphorine(0.10 mL, 0.34 mmol). The resulting mixture was shaken at rt for 2 days,then was drained and washed with DMF (4×2 mL), MeOH (4×2 mL) and CH₂Cl₂(4×2 mL).

The resin was then treated with 10% (v/v) TFA/CH₂Cl₂. The mixture wasshaken for 1 h, filtered and washed with CH₂Cl₂ (2×0.5 mL). The combinedfiltrates were concentrated under vacuum to afford the title compound asa beige solid (7.7 mg, 100%, HPLC purity>95%). HRMS (ESI), (M−H)⁻ forC₂₀H₂₄SClN₂O₃ calcd: 407-1206, found: 407.1201; ¹H NMR (CDCl₃) δ 7.64(d, 2H, J=8.0), 7.44 (d, 2H, J=8.0), 7.22 (d, 2H, J=8.0), 7.08 (d, 2H,J=8.0), 6.29 (br s, 1H), 5.34 (br s, 1H), 4.53 (d, 1H, J=15.2), 4.34 (d,1H, J=15.2), 4.27 (t, 1H, J=7.2), 2.32 (s, 3H), 1.84 (m, 1H), 1.30 (m,1H), 1.21 (m, 1H), 0.75 (d, 3H, J=6.8), 0.67 (d, 3H, J=6.8); IR (KBr)3467, 3367, 2956, 2869, 1694, 1670, 1340, 1160 cm⁻¹.Exemplification of Reaction Scheme 2

(2R)-2-(4-Methoxybenzylamino)-4-methylpentanoic acid amide

A solution of D-leucinamide hydrochloride (2.8 g, 16.8 mmol), andp-anisaldehyde (2.29 g, 16.8 mmol) in methanol (150 mL) was treated withanhydrous ZnCl₂ (538 mg, 5 mmol). The resulting suspension was thentreated with NaCNBH₃ (1.05 g, 16.8 mmol) portion wise and heated atreflux for 3 h. The reaction was cooled to rt, quenched with saturatedNaHCO₃ (3 mL), diluted with EtOAc (500 mL), and washed with brine.Concentration afforded the crude benzyl amine as a white wax, which wascarried on without further purification (3.57 g, 84%). MS (ESI), (M+H)⁺251.4; ¹H NMR (CDCl₃) δ 7.20 (d, 2H, J=6.6), 7.10 (br s, 2H), 6.88 (d,2H, J=8.4), 5.30 (br s, 1H), 3.80 (s, 3H), 3.63 (dd, 2H, J=4.5, 12),1.44-1.65 (m, 3H), 0.95 (d, 3H, J=6.3), 0.80 (d, 3H, J=6.3).

(2R)-2-[N-(4-Chlorobenzenesulfonyl)-N-(4-methoxybenzyl)amino]-4-methylpentanoicacid amide (Example 1)

(2R)-2-[N-(4-Methoxybenzy)lamino]-4-methylpentanoic acid amide (3.57 g,14.3 mmol) was dissolved in CH₂Cl₂ (100 mL) and treated with Et₃N (4.2mL, 29 mmol) and 4-chlorobenzenesulfonyl chloride (3.6 g, 17 mmol) at rtfor 18 h. The solvents were removed and the residue was taken into EtOAc(500 mL). The organic solution was washed with H₂O, brine, dried overMgSO₄, and concentrated. The resulting material was then furtherpurified by flash chromatography (SiO₂, 1% MeOH/CH₂Cl₂) to afford thetitle compound (2.4 g) as a slightly colored solid in 40% yield. MS(ESI), (M−H)⁻ 422.9; ¹H NMR (CDCl₃) δ 7.63 (d, 2H, J=7.0), 7.42 (d, 2H,J=7.0), 7.25 (d, 2H, J=8.0), 6.79 (d, 2H, J=8.0), 6.25 (br s, 1H), 5.35(br s, 1H), 4.36 (dd, 2H, J=5.0, 15), 4.26 (t, 1H, J=7.2), 3.78 (s, 3H),1.83 (m, 1H), 1.18-1.34 (m, 2H), 0.75 (d, 3H, J=7.0), 0.67 (d, 3H,J=7.0); IR (KBr) 3480, 2959, 1693, 1674, 1514, 1333, 1158 cm⁻¹.Exemplification of Reaction Scheme 3

(2R)-2-[N-(4-Morpholinohexyl)-N-(4-chlorobenzenesulfonlyl)amino]-4-methylpentanoicacid amide (Example 25)

A solution of(2R)-2-[N-(4-bromohexyl)-N-(4-chlorobenzenesulfonyl)amino]-4-methylpentanoicacid amide (Example 24; prepared as described in Reaction Scheme 1; 0.20g, 0.44 mmol), Et₃N (0.25 mL, 1.7 mmol), and morpholine (150 mg, 1.7mmol) in CH₂Cl₂ (2 mL) was stirred at rt for 18 h. The reaction was thenconcentrated to give a crude white wax which was purified by flashchromatography (SiO₂, 85% EtOAc/5% hexanes/10% MeOH) to afford the titlecompound (112 mg) as a white solid in 54% yield. MS (ESI), (M+H)⁺ 474.4;¹H NMR (DMSO-d₆) δ 7.82 (d, 2H, J=8.0), 7.64 (d, 2H, J=8.0), 7.42 (br s,1H) 6.99 (s, 1H), 4.25 (m, 1H), 3.51-3.60 (br s, 4H), 3.18-3.41 (m, 2H),2.25-2.35 (br s, 4H), 2.27 (m, 2H) 1.15-1.62 (m, 9H), 0.80 (d, 6H,J=6.0).Exemplification of Reaction Scheme 4

(2R)-2-[N-(4-Chlorobenzenesulfonyl)-N-(4-aminobenzyl)amino]-4-methylpentanoicacid amide (Example 48)

(2R)-(2-[N-(4-Chlorobenzenesulfonyl)-N-(4-nitrobenzyl)amino]-4-methylpentanoicacid amide (Compound of Example 24; prepared as described in ReactionScheme 1; 2.8 g, 6.6 mmol) was suspended with 10% Pd/C (1 g) and conc.HCl (1 mL) in MeOH (100 mL) and placed under a hydrogen atmosphere at 40psi for 1 h. The suspension was filtered through Celite and thenconcentrated to give the title compound as a tan solid (2.4 g, 88%yield). MS (ESI), (M+H)⁺ 410.1; ¹H NMR (CDCl₃) δ 7.80 (d, 2H, J=8.5),7.63 (d, 2H, J=8.5), 7.52 (br s, 1H), 7.46 (d, 1H, J=8.0), 7.26 (d, 1H,J=8.0), 7.02 (br s, 1H), 4.70 (dd, 2H, J=50, 18), 4.30-4.41 (m, 1H),3.67 (br s, 2H), 1.28-1.33 (m, 3H), 0.86 (d, 3H, J=7.0), 0.57 (d, 3H,J=7.0).

(2R)-2-[N-(4-Chlorobenzenesulfonyl)-N-(4-methylaminobenzyl)amino]-4-methylpentanoicacid amide (Example 51)

A solution of(2R)-2-[N-(4-chlorobenzenesulfonyl)-N-(4-aminobenzyl)amino]-4-methyl-pentanoicacid amide (Example 48, 400 mg, 1 mmol), Et₃N (0.16 mL, 1.1 mmol),dimethylsulfate (139 mg, 1.1 mmol) in 25 mL of toluene was stirred at rtfor 18 h. The reaction was concentrated, then taken into EtOAc andwashed with H₂O, brine, dried over K₂CO₃ and concentrated to give acrude mixture of starting material and product. The material was furtherpurified by flash chromatography (SiO₂, 35% EtOAc/hexanes) to afford thetitle compound, 195 mg, in 46% yield. MS (ESI), (M+H)⁺ 424.1; ¹H NMR(CDCl₃) δ 7.65 (d, 2H, J=8.0), 7.58 (d, 2H, J=8.2), 7.47 (d, 2H, J=8.0),7.31 (d, 2H, J=8.5), 6.24 (br s, 1H), 5.16 (br s, 1H), 4.50 (dd, 2H,J=50, 17), 4.27 (t, 1H, J=10), 2.44 (s, 3H), 1.74-1.83 (m, 1H),1.25-1.33 (m, 1H), 0.93-1.01 (m, 1H), 0.74 (d, 3H, J=7.0), 0.63 (d, 3H,J=7.0).

(2R)-2-[N-(4-Chlorobenzenesulfonyl)-N-(4-dimethylaminobenzyl)amino]-4-methylpentanoicacid amide (Example 65)

(2R)-2-[N-(4-Chlorobenzene-sulfonyl)-N-(4-aminobenzyl)amino]-4-methyl-pentanoicacid amide (Example 48, 0.10 g, 0.22 mmol) was dissolved in DMF (5 mL).To this solution was added iodomethane (62 mg, 0.44 mmol), and cesiumcarbonate (220 mg, 0.66 mmol). The reaction was then stirred at 40° C.for 18 h. The reaction was poured into EtOAc and water. The organic wascollected, dried over MgSO₄, and concentrated to an oily residue. Theresidue was further purified (Biotage 40S, loaded in CH₂Cl₂, eluted in25% EtOAc/hexanes) to yield a yellow powder (15 mg, 16%). MS (ESI),(M+H)⁺ 438.1; ¹H NMR (DMSO-d₆, 500 MHz) δ 7.74 (dd, 2H, J=1.9, 6.7),7.54 (dd, 2H, J=1.9, 6.8), 7.43 (s, 1H), 7.16 (d, 2H, J=8.6), 7.01 (s,1H), 6.61 (d, 2H, J=8.8), 4.59 (q, 2H, J=16, 25), 4.34 (dd, 1H, J=5.0,9.3), 2.85 (s, 6H), 1.27-1.47 (m, 3H), 0.80 (d, 3H, J=5.9), 0.52 (d, 3H,J=6.1).Exemplification of Reaction Scheme 5

{N-[(1R)-1-Carbamoyl-3-methyl-butyl]-N-(4-chlorobenzenesulfonyl)amino}aceticacid tert-butyl ester (Example 46)

(2R)-2-(4-Chlorobenzenesulfonylamino)-4-methylpentanoic acid amide (3.00g, 9.87 mmol) was dissolved in DMF (50 mL). To the solution was addedpotassium carbonate (6.0 g, 39 mmol) and bromoacetic acid tert-butylester (6.0 mL, 39 mmol). The solution was heated to 70° C. for 3 h. Thereaction was quenched with EtOAc and saturated NaHCO₃. The organic layerwas washed with brine, dried over MgSO₄, and concentrated. The crude oilwas further purified on a Biotage 40M (loaded in CH₂Cl₂, eluted in 30%EtOAc/hexanes) to afford a white powder (1.2 g, 35%). MS (ESI), (M+H)⁺446.3; ¹H NMR (CDCl₃) δ 7.76 (d, 2H, J=8.0), 7.52 (d, 2H, J=8.0), 6.61(br s, 1H) 5.45 (s, 1H), 4.15-4.18 (m, 1H), 3.09-3.24 (m, 2H), 2.50-2.58(m, 4H), 2.31-2.39 (m, 2H), 1.92-1.99 (m, 1H), 1.15-1.59 (m, 8H),1.00-1.04 (m, 7H), 0.71-0.74 (m, 6H).

{N-[(1R)-1-Carbamoyl-3-methyl-butyl]-N-(4-chlorobenzenesulfonyl)amino}aceticacid (Example 59)

Trifluoroacetic acid (15 mL) was added to a solution of{N-[(1R)-1-carbamoyl-3-methyl-butyl]-N-(4-chlorobenzenesulfonyl)amino}aceticacid tert-butyl ester (0.50 g, 1-2 mmol) in CH₂Cl₂ (15 mL). The reactionwas stirred at rt for 4 h. The reaction was then concentrated to a whitesolid (0.40 g, 92%), which was used without further purification. MS(ESI), (M+H)⁺ 363.1; ¹H NMR (DMSO-d₆, 500 MHz) δ 7.90 (dd, 2H, J=2.0,6.8), 7-65 (dd, 2H, J=2.0, 6.8), 7.60 (s, 1H), 7-06 (s, 1H), 4.32 (d,1H, J=18), 4.12 (t, 1H, J=8.0), 4.02 (d, 1H, J=18), 1.55-1.65 (m, 1H),1.35-1.45 (m, 2H), 0.78 (d, 3H, J=6.1), 0.73 (d, 3H, J=6.1).

(2R)-2-[N-(4-Chlorobenzenesulfonyl)-N-(cyclopropylcarbamoylmethyl)amino]-4-methyl-pentanoicacid amide (Example 88)

To a solution of{N-[(1R)-1-carbamoyl-3-methyl-butyl]-N-(4-chlorobenzenesulfonyl)amino}aceticacid (Example 59, 175 mg, 0.480 mmol), cyclopropylamine (41 uL, 0.58mmol) in CH₂Cl₂ (3 mL) was added 1-hydroxybenzotriazole (47 mg, 0.72mmol), and 1,3-dicyclohexylcarbodiimide (144 mg, 0.720 mmol). Thereaction was stirred for 18 h at rt, and then was poured into anEtOAc/water mixture. The organic layer was separated, dried over MgSO₄,and concentrated to a clear oil residue. The residue was furtherpurified by Biotage 40S (eluted in 40% EtOAc in hexanes) to afford awhite solid (54 mg, 29%). MS (ESI), (M+H)⁺ 402.2; ¹H NMR (CDCl₃, 500MHz) δ 7.85 (dd, 2H, J=1.9, 8.9), 7.50 (dd, 2H, J=2.0, 8.7), 7.40 (br s,1H), 6.55 (br s, 1H), 6.30 (br s, 1H), 4.23 (dd, 1H, J=2.9, 8.9), 3.92(d, 1H, J=17), 3.83 (d, 1H, J=17), 2.68-2.73 (m, 1H), 1.75-1.83 (m, 1H),1.50-1.57 (m, 1H), 1.40-1.49 (m, 1H), 0.88 (d, 3H, J=6.4), 0.87 (d, 3H,J=6.7), 0.80 (d, 2H, J=7.0), 0.51 (t, 2H, J=4.0).Exemplification of Reaction Scheme 6

4-{[N-((1R)-1-Carbamoyl-3-methyl-butyl)-N-(4-chlorobenzenesulfonyl)amino]-methyl}-benzoicacid (Example 89)

A solution of the compound of Example 61[4-{[N-((1R)-1-carbamoyl-3-methyl-butyl)-N-(4-chlorobenzenesulfonyl)amino]-methyl}-benzoicacid methyl ester, 354 mg, 0.782 mmol] was dissolved in methanol (4 mL).A solution of 5 N NaOH (1 mL) was added, followed by enough THF (1 mL)to achieve homogeneity. After 1 h, an additional aliquot of 5 N NaOH (1mL) was added, and stirring was continued for 2.5 h. The solution wasacidified to pH 2 with 1 N HCl and extracted with CHCl₃ (2×). Thecombined organic layers were dried (Na₂SO₄) and concentrated to give awhite solid (343 mg, 100%). MS (ESI), (M+H)⁺ 439.17; ¹H NMR (CDCl₃, 300MHz) δ 7.91 (d, 2H, J=8.2), 7.81-7.84 (m, 3H), 7.56 (d, 2H, J=8.6), 7.49(d, 2H, J=8.2), 6.55 (br s, 1H), 5.10 (d, 1H, J=15.4), 4.23 (dd, 1H,J=4.6, 9.7), 4.05 (d, 1H, J=15.4), 2.04-2-14 (m, 1H), 1.20-1.31 (m, 1H),0.80-0.89 (m, 1H), 0.74 (d, 3H, J=6.6), 0.68 (d, 3H, J=6.6).

(2R)-2-{N-(4-Chlorobenzenesulfonyl)-N-[4-(morpholine-4-carbonyl)-benzyl]amino}-4-methyl-pentanoicacid amide (Example 101)

To a 0° C. solution of4-{[N-((1R)-1-carbamoyl-3-methyl-butyl)-N-(4-chlorobenzenesulfonyl)amino]-methyl}benzoicacid (50.0 mg, 0.114 mmol) in DMF (0.3 mL) was added morpholine (12.9mg, 0.148 mmol), followed by 1-hydroxybenzotriazole (18.5 mg, 0.137mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (26.2mg, 0.137 mmol), and iPr₂NEt (26 μL, 0.15 mmol). After 2 h, the solutionwas warmed to rt. After 4 h, the solution was poured into 10% aq. citricacid and extracted with EtOAc (2×). The combined organic layers werewashed sequentially with water and sat. aq. NaHCO₃, then dried (MgSO₄)and concentrated. Flash column chromatography (SiO₂, 40 to 100%EtOAc/hexanes) gave the title compound as a white solid (46.0 mg, 79%).MS (ESI), (M+H)⁺ 508.22; ¹H NMR (CDCl₃, 300 MHz) δ 7.68 (d, 2H, J=8.6),7.29-7.47 (m, 6H), 6.38 (br s, 1H), 5.75 (br s, 1H), 4.65 (d, 1H,J=16.0), 4.42 (d, 1H, J=16.0), 4.32 (t, 1H, J=7.5), 3.30-3.85 (br in,8H), 1.69-1.78 (m, 1H), 1.28-1.37 (m, 1H), 1.08-1.14 (m, 1H), 0.76 (d,3H, J=6.5), 0.63 (d, 3H, J=6.6).Exemplification of Reaction Scheme 7

4-{[N-((1R)-1-Carbamoyl-3-methyl-butyl)-N-(4-chlorobenzenesulfonyl)amino]-methyl}-piperidine-1-carboxylicacid tert-butyl ester (Example 92)

To a solution of (2R)-2-(4-chlorobenzenesulfonylamino)-4-methylpentanoicacid amide (4.2 grams, 14 mmol) in DMF (50 mL) was added cesiumcarbonate (13.6 grams, 417 mmol). To this reaction was added4-(toluene-4-sulfonyloxymethyl)-piperidine 1-carboxylic acid tert-butylester (ref.: Gilissen, C.; Bormans, G.; De Groot, T.; Verbniggen, A. J.Labeled Cmpd. Radiopharm. 1999, 42, 1289; 10.4 g, 282 mmol). Thereaction was stirred at 70° C. for 18 h. The reaction was then quenchedwith sat. aq. NaHCO₃ and extracted with EtOAc. The organic layer wascollected, washed with brine, dried over MgSO₄, and concentrated to aclear oil. The oil was then purified on a Biotage 40S (eluted with 30%EtOAc in hexanes) to afford a white solid (3.0 g, 44%). MS (ESI), (M+H)⁺502.1; ¹H NMR (DMSO-d₆, 500 MHz) δ 7.86 (dd, 2H, J=2.0, 6.8), 7.65 (dd,2H, J=2.0, 6.8) 7.37 (br s, 1H), 7.07 (br s, 1H), 4.19 (t, 1H, J=7.6),3.92 (br s, 2H), 3.35 (dd, 1H, J=15, 6.8), 3.05 (dd, 1H, J=15, 8.1),1.85 (br s, 1H), 1.50-1.70 (m, 4H), 1.38 (s, 9H), 1.10-1.20 (m, 1H),0.80-1.00 (m, 3H), 0.82 (d, 6H, J=7.6).

(2R)-2-[N-(4-Chlorobenzenesulfonyl)-N-(piperidin-4-ylmethyl)amino]-4-methyl-pentanoicacid amide (Example 126)

To a solution of4-{[N-((1R)-1-carbamoyl-3-methyl-butyl)-N-(4-chlorobenzenesulfonyl)amino]-methyl}-piperidine-1-carboxylicacid tert-butyl ester (Example 92, 2.6 grams, 5.2 mmol) in CH₂Cl₂ (25mL) was added trifluoroacetic acid (10 mL). The reaction was stirred atrt for 1 h and then was concentrated to give a white solid (1.6 grams,84%). MS (ESI), (M+H)⁺ 402.15; ¹H NMR (DMSO-d₆, 500 MHz), δ 7-87 (d, 2H,J=8.5), 7.66 (d, 2H, J=8.6), 7.41 (s, 1H), 7.04 (s, 1H), 4.17 (t, 1H,J=7.3), 3.40-3.50 (m, 1H), 3.20-3.25 (m, 1H), 3.03-3.10 (m, 1H),2.65-2.80 (m, 2H), 1.85-2.00 (m, 1H), 1.20-1.85 (m, 2H), 1.45-1.60 (m,1H), 1.30-1.40 (m, 1H), 1.10-1.30 (m, 4H), 0.75-0.90 (m, 1H), 0.82 (d,3H, J=7.3), 0.80 (d, 3H, J=7.0).

(2R)-2-{N-(4-Chlorobenzenesulfonyl)-N-[1-(pyridine-4-carbonyl)-piperidin-4-ylmethyl]-amino}-4-methyl-pentanoicacid amide (Example 278)

To a solution of(2R)-2-[N-(4-chlorobenzenesulfonyl)-N-(piperidin-4-ylmethyl)amino]-4-methyl-pentanoicacid amide (Example 126, 0.10 g, 0.22 mmol) and Et₃N (0.06 mL, 0-5 mmol)in CH₂Cl₂ (3.0 mL) was added isonicotinoyl chloride hydrochloride (56mg, 0.32 mmol). The reaction was stirred at rt for 18 h and then waspoured into a mixture of EtOAc and sat. aq. NaHCO₃. The organic solutionwas separated and washed with brine, dried over MgSO₄, and concentratedto an oily residue. The residue was purified on a Biotage 10M (elutedwith 80% EtOAc/hexanes) to give a white solid (36 mg, 30%). MS (ESI),(M+H)⁺ 509.20; ¹H NMR (CDCl₃, 500 MHz) δ 8.66 (br s, 2H), 7.80 (d, 1H,J=8.6), 7.73 (d, 2H, J=8.5), 7.51 (d, 2H, J=7.6), 7.41 (br s, 1H), 6.64(br s, 1H), 5.35 (br s, 1H), 4-70 (br s, 1H), 4.10 (br s, 1H), 3.71 (brs, 1H), 3.33 (br s, 1H), 3.02 (dd, 2H, J=4.8, 16), 2.70-2.85 (br s, 1H),1.50-2.09 (m, 5H), 1.18-1.33 (m, 4H), 0.73 (d, 3H, J=6.7), 0.68 (d, 3H,J=6.5).

4-{[N-((1R)-1-Carbamoyl-3-methyl-butyl)-N-(4-chlorobenzenesulfonyl)amino]-methyl}-piperidine-1-carboxylicacid phenethylamide (Example 256)

To a solution of(2R)-2-[N-(4-chlorobenzenesulfonyl)-N-(piperidin-4-ylmethyl)amino]-4-methyl-pentanoicacid amide (Example 126, 0.10 g, 0.22 mmol) and Et₃N (32 μL, 0.25 mmol)in CH₂Cl₂ (3.0 mL) was added (2-isocyanato-ethyl)-benzene (0.040 mL,0.30 mmol). The reaction was stirred at rt for 18 h and then was pouredinto sat. aq. NaHCO₃ and extracted with EtOAc. The organic layer waswashed with brine, dried over MgSO₄, and concentrated to an oilyresidue. The residue was further purified on a Biotage system (elutedwith 75% EtOAc/hexanes) to afford the desired product as a white solid(67 mg, 52%). MS (ESI), (M+H)⁺ 549.00; ¹H NMR (CDCl₃, 500 MHz) δ 7.71(d, 2H, J=8.6), 7.71 (d, 2H, J=8.9), 7.15-7-35 (m, 5H), 6.64 (s, 1H),5.86 (s, 1H), 4.15 (dd, 1H, J=5.2, 9.5), 3.88 (d, 1H, J=13), 3.76 (d,1H, J=13), 3.46 (t, 2H, J=6.7), 3.21-3.29 (m, 1H), 2.97 (dd, 1H, J=4.6,14), 2.65-2.85 (m, 4H), 1.75-1.95 (m, 3H), 1.00-1.30 (m, 5H), 0.75-0.80(m, 1H), 0.72 (d, 3H, J=6.7), 0.67 (d, 3H, J=6.7).

(2R)-2-(N-(4-Chlorobenzenesulfonyl)-N-{1-[2-(4-cyanophenyl)-2-oxo-ethyl]-piperidin-4-ylmethyl}-amino)-4-methyl-pentanoicacid amide (Example 286)

To a solution of(2R)-2-[N-(4-chlorobenzenesulfonyl)-N-(piperidin-4-ylmethyl)amino]-4-methyl-pentanoicacid amide (Example 126, 0.050 g, 0.12 mmol) and Et₃N (0.040 mL, 0.30mmol) in CH₂Cl₂ (2.0 mL) was added 4-(2-chloro-acetyl)-benzonitrile (55mg, 0.30 mmol). The reaction was stirred at rt for 18 h and then wasconcentrated to residue. The residue was purified on a Biotage system(eluted with 80% EtOAc/hexanes) to produce 29 mg (48%) of the desiredproduct as a white solid. MS (ESI), (M+H)⁺ 545.16; ¹H NMR (CDCl₃, 500MHz) δ 7.72 (d, 2H, J=8.5), 7.50-7.65 (m, 2H), 7.50 (d, 2H, J=7.0),7.35-7-45 (m, 2H), 6.67 (s, 1H), 5.32 (s, 1H), 4.14 (dd, 1H, J=5.0,9.0), 3.52 (br s, 1H), 3.28 (t, 1H, J=14), 2.97 (dd, 1H, J=3.5, 14),2.82 (br s, 1H), 1.00-2.00 (m, 10H), 0.71 (d, 3H, J=6.5), 0.66 (d, 3H,J=6.5).Exemplification of Reaction Scheme 8

(2R)-2-{N-(4-Chlorobenzenesulfonyl)-N-[4-(tetrahydro-pyran-2-yloxymethyl)-benzyl]-amino}-4-methyl-pentanoicacid amide

(2R)-2-(4-Chlorobenzenesulfonylamino)-4-methylpentanoic acid amide (6.35g, 196 mmol), Cs₂CO₃ (5.62 g, 196 mmol), and2-[(4-bromomethyl)benzyl]oxy)tetrahydropyran (5.62 g, 196 mmol) inacetonitrile (200 mL) were heated to reflux for 1 h. The reaction wasfiltered hot with suction through Celite. The filtrate was reduced invacuo to a white foam (9.5 g, 96%). The foam was used as is in the nextreaction. MS (ESI), (M+H)⁺ 510.9, ¹H NMR (CDCl₃) δ 7.83 (d, 2H, J=8.0),7.75 (d, 2H, J=8.0), 7.39 (d, 2H, J=8.0), 7.24 (d, 2H, J=8.0), 6.25 (brs, 1H), 5.35 (br s, 1H), 4.82 (d, 1H, J_(ab)=12), 4.65 (m, 1H), 4.52 (d,1H, J_(ab)=12), 4.30 (d, 1H, J_(ab)=16), 4.20 (d, 1H, J_(ab)=16), 3.74(m, 2H), 3.46 (m, 1H), 1.89 (m, 1H), 1.66 (m, 6H), 0.97 (d, 3H, J=7.0),0.94 (d, 3H, J=7.0).

(2R)-2-[N-(4-Chlorobenzenesulfonyl)-N-(4-hydroxymethyl)benzylamino]-4-methyl-pentanoicacid amide (Example 95)

To a solution of(2R)-2-[N-(4-chlorobenzenesulfonyl)-N-[4-(tetrahydropyran-2-yloxymethyl)benzylamino]-4-methyl-pentanoicacid amide (9.5 g, 186 mmol) in methanol (200 mL) was added a catalyticamount of p-toluenesulfonic acid. The mixture was stirred overnight atrt. The solvent was removed in vacuo. The resulting foam was dissolvedin CH₂Cl₂ (100 mL) washed with 1 N NaOH, H₂O, brine, and dried overMgSO₄. The filtrate solvent was removed in vacuo. The resulting foam wascrystallized from hot hexane affording the product as a white solid (7.7g) in 92% yield. MS (ESI), (M+H)⁺ 425.17, ¹H NMR (CDCl₃) δ 7.68 (d, 2H,J=7.0), 7.46 (d, 2H, J=7.0), 7.33 (d, 2H, J=8.0), 7.28 (d, 2H, J=8.0),6.26 (br s, 1H), 5.35 (br s, 1H), 4.67 (br s, 2H), 4.59 (d, 1H,J_(ab)=16), 4.37 (d, 1H, J_(ab)=16), 4.26 (t, 1H, 7.0), 1.86-1.80 (m,2H), 1.34-1.28 (m, 1H), 1.16-1.10 (m, 1H), 0.96 (d, 3H, J=7.0), 0.93 (d,3H, J=7.0).

Methanesulfonic acid4-{[N-((1R)-1-carbamoyl-3-methyl-butyl)-N-(4-chlorobenzene-sulfonyl)-amino]methyl}benzylester

To a stirred solution of(2R)-2-[N-(4-chloro-benzenesulfonyl)-N-(4-hydroxymethyl-benzyl)amino]-4-methyl-pentanoicacid amide (1.5 g, 3.5 mmol) in CH₂Cl₂ (15 mL) cooled to 0° C. was addedEt₃N (0.74 mL, 5.3 mmol). A solution of methanesulfonyl chloride (0.29mL, 3.5 mmol) in 5 mL CH₂Cl₂ was added dropwise and the reaction wasallowed to stir at 0° C. for 1 h. The reaction mixture was diluted with25 mL CH₂Cl₂, quickly washed with 1 N HCl, brine, and dried by passingthe organic phase through a cotton plug. The solvent was removed invacuo affording the title compound in quantitative yield. The resultingfoam was used as is in subsequent reactions. MS (EST), (M-95)⁺, 409.15¹H NMR (CDCl) δ 7.70 (d, 2H, J=8.0), 7.48 (d, 2H, J=8.0), 7.41 (d, 2H,J=8.0), 7.38 (d, 2H, J=8.0), 6.27 (br s, 1H), 5.32 (br s, 1H), 5.24 (s,2H), 4.64 (d, 1H, J_(ab)=16), 4.43 (d, 1H, J_(ab)=16), 4.33 (t, 1H,J=6), 2.90 (s, 3H), 1.90 (m, 1H), 1.60 (m, 2H), 0.96 (d, 3H, J=7.0),0.91 (d, 3H, J=7.0)

(2R)-2-[N-(4-Chlorobenzenesulfonyl)-N-(4-dimethylaminomethylbenzyl)amino]-4-methyl-pentanoicacid amide (Example 110)

To a stirred solution of methanesulfonic acid4-{[N-((1R)-1-carbamoyl-3-methyl-butyl)-N-(4-chlorobenzenesulfonyl)amino]-methyl}-benzylester (150 mg, 0.298 mmol) in (3 mL) CH₂Cl₂ at 0° C. was added 1equivalent of Et₃N, followed by dimethylamine (0.3 mL, 2 M in THF). Thereaction was stirred overnight at rt. The mixture was diluted withCH₂Cl₂, washed with H₂O, brine, dried over MgSO₄, and concentrated togive an amber glass. Purification by flash chromatography (SiO₂, 10%MeOH/CH₂Cl₂) afforded the title compound (95 mg) in 71% yield. MS (EST),(M+H)⁺ 452.23, ¹H NMR (CDCl₃) δ 7.94 (d, 2H, J=8.0), 7.74 (d, 2H,J=8.0), 7.63 (d, 2H, J=8.0) 7.38 (d, 2H, J=8.0), 6.23 (br s, 1H), 5.35(br s, 1H), 4.22 (d, 1H, J_(ab)=16), 4.14 (d, 1H, J_(ab)=16), 3.28-3.23(m, 3H), 2.17 (br s, 6H), 1.95 (m, 1H), 1.55 (m, 2H), 0.96 (d, 3H,J=7.0), 0.93 (d, 3H, J=7.0).Exemplification of Reaction Scheme 9

(2R)-2-[N-(4-Acetylaminobenzyl)-N-(4-chlorobenzenesulfonyl)amino]-4-methyl-pentanoicacid amide (Example 163)

A solution of the compound of Example48[(2R)-2-[N-(4-chlorobenzenesulfonyl)-N-(4-aminobenzyl)amino]-4-methyl-pentanoicacid amide (250 mg, 0.60 mmol) and Et₃N (120 mg, 1.2 mmol) in CH₂Cl₂ (20mL) was treated with acetyl chloride (56 mg, 0.72 mmol). After stirringfor 18 h, the reaction was concentrated, chromatographed using silicagel flash chromatography (1% methanol/CH₂Cl₂) to afford the titledcompound (110 mg, 41%). MS (ESI), (M−H)⁻ 422.9; ¹H NMR (CDCl₃) δ 7.67(d, 2H, J=8.0), 7.28-7.46 (m, 6H), 7.12 (br s, 1H), 6.24 (br s, 1H),5.19 (br s, 1H), 4.48 (dd, 2H, J=50, 15), 4.27 (t, 1H, J=7.0), 2.18 (s,3H), 1.80-2.01 (m, 1H), 1.12-1.32 (m, 2H), 0.75 (d, 3H, J=7.0), 0.67 (d,3H, J=7.0).

(2R)-2-[N-(4-Chlorobenzenesulfonyl)-N-(4-{[(2-dimethylamino-acetyl)-methyl-amino]-methyl}-benzyl)-amino]-4-methyl-pentanoicacid amide (Example 272)

(2R)-2-[N-(4-Chlorobenzenesulfonyl)-N-(4-methylaminomethyl-benzyl)-amino]-4-methyl-pentanoicacid amide (75 mg, 0.17 mmol), (α-dimethylamino)acetic acid (18 mg, 0.17mmol), 1-hydroxybenzotriazole (24 mg, 0.17 mmol), and1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (33 mg,0.17 mmol) were combined in 3 mL CH₂Cl₂ and stirred overnight. Thereaction mixture was diluted with 5 mL CH₂Cl₂ and washed with 1 N NaOHand brine. The organic phase was dried by filtering through cotton andthe solvent was removed in vacuo. Purification via preparative HPLCafforded the title compound (61 mg) in 68% yield. MS (ESI), 523.4 (M+H)⁺¹H NMR (CDCl₃) δ 8.02 (d, 2H, J=8.0), 7.71 (d, 2H, J=8.0), 7.37 (d, 2H,J=8.0), 7.28 (d, 2H, J=8.0), 6.23 (br s, 1H), 5.51 (br s, 1H), 4.46 (s,2H), 4.70 (d, 1H, J_(ab)=16), 4.33 (d, 1H, J_(ab)=16), 3.25 (t, 1H,J=6.0), 2.69 (s, 3H), 2.63 (s, 2H), 2.20 (s, 6H), 1.95 (m, 1H), 1.60 (m,2H), 0.98 (d, 3H, J=7.0), 0.94 (d, 3H, J=7.0).Exemplification of Reaction Scheme 10

(2R)-2-[N-(4-Chlorobenzenesulfonyl)-N-(2-dimethylaminopyridin-5-ylmethyl)amino]-4-methylpentanoicacid amide TFA salt (Example 254)

A solution of(2R)-2-[N-(4-chlorobenzenesulfonyl)-N-(2-chloropyridin-5-ylmethyl)amino]-4-methylpentanoicacid amide (prepared via Reaction Scheme 1, 18 mg, 41 mmol) indimethylamine/THF (2 M, 20 mL, 40 mmol) was stirred at 95° C. for 30 hin a pressure vessel. Five mL of reaction mixture (25% of total reactionvolume) was purified by reverse phase preparative HPLC (YMC S5, ODS,MeOH-water-TFA) to afford the title compound as a white foam (17 mg, 30%yield). HRMS (ESI), (M−H)⁻ for C₂₀H₂₆SClN₄O₃ calcd: 437.1426, found:437.1420; ¹H NMR (CDCl₃): δ 8.04 (s, 1H), 8.03 (d, 1H, J=9.8), 7.76 (d,2H, J=7.6), 7.54 (d, 2H, J=7.6), 6.83 (d, 1H, J=9.8), 6.62 (br s, 1H),6.40 (br s, 1H), 4.64 (d, 1H, J=15.9), 4.29 (m, 1H), 4.18 (d, 1H,J=15.9), 3.30 (s, 6H), 1.84 (m, 1H), 1.29 (m, 1H), 0.93 (m, 1H), 0.77(d, 3H, J=6.5), 0.72 (d, 3H, J=6.5).Exemplification of Reaction Scheme 11

(2R)-2-[N-(4-Allyloxy-3-fluorobenzyl)-N-(4-chlorobenzenesulfonyl)amino]-4-methyl-pentanoicacid amide

To a solution of(2R)-2-(4-chlorobenzenesulfonylamino)-4-methyl-pentanoic acid amide(1.00 g, 3.29 mmol), and Cs₂CO₃ (1.29 g, 3.95 mmol) in DMF (25 mL) wasadded 1-allyloxy-4-bromomethyl-2-fluorobenzene (ref.: Graham, Samuel L;et al., Eur. Pat. Appl. (1992): EP 487270; 0.88 g, 3.67 mmol). Theresulting solution was stirred at rt for 18 h. The reaction was thendiluted with 9:1 EtOAc:hexanes (350 mL) and washed with H₂O (4×200 mL),brine, and dried over Na₂SO₄, to afford the titled compound (393 mg) asa white solid in 26% yield. MS (ESI), (M+H)⁺ 469.1; ¹H NMR (CDCl₃) δ7.66 (d, 2H, J=8.1), 7.45 (d, 2H, J=8.1), 7.11 (d, 1H, J=12.0), 6.98 (m,1H), 6.84 (t, 1H, J=8.0), 6.22 (br s, 1H), 6.04 (m, 2H), 5.42 (m, 1H),5.16 (br s, 1H), 4.59 (m, 2H), 4.40 (m, 3H), 1.83 (m, 1H), 1.32 (m, 1H),1.14 (m, 1H), 0.76 (d, 3H, J=7.0), 0.68 (d, 3H, J=7.0).

(2R)-2-{N-(4-Chlorobenzenesulfonyl)-N-[3-fluoro-4-(2-morpholin-4-yl-ethoxy)-benzyl]-amino}-4-methyl-pentanoicacid amide (Example 427)

A mixture of the allyloxy intermediate (0.39 g, 0.84 mmol) from above,osmium tetraoxide (0.01 g, 0.04 mmol), and trimethylamine N-oxide (0.140g, 1.81 mmol) was dissolved in acetone (10 mL) and stirred for 4 h atrt. The solution was concentrated in vacuo and redissolved in 1.5:1dioxane:H₂O (15 mL). Sodium periodate (0.22 g, 1.0 mmol) was added andthe solution was stirred at rt for 18 h. The reaction was then dilutedwith EtOAc (200 mL) and washed with H₂O, brine, dried over Na₂SO₄ andconcentrated to give(2R)-{N-(4-chlorobenzenesulfonyl)-N-[3-fluoro-4-(2-oxo-ethoxy)-benzyl]-amino}-4-methyl-pentanoicacid amide as a crude beige solid. This crude material was taken ontothe next step without further purification.(2R)-2-{N-(4-Chlorobenzenesulfonyl)-N-[3-fluoro-4-(2-oxo-ethoxy)-benzyl]-amino}-4-methyl-pentanoicacid amide (0.16 g, 0.34 mmol) and morpholine (0.090 g, 1.0 mmol) wasdissolved in EtOH (5 mL) and heated to 80° C. for approximately 15 min.The oil bath was removed and sodium triacetoxyborohydride (0.290 g, 1.36mmol) was added and the slurry was stirred at rt for 16 h. The solutionwas concentrated to dryness, taken up in brine, extracted with EtOAc(2×100 mL), dried over Na₂SO₄, and concentrated in vacuo to give a crudeorange residue. Further purification by Prep HPLC (20×100 mm YMC S5 ODSC-18 column, 25 mL/min, 0-100% MeOH/H₂O 0.1% TFA 15 min) afforded as aTFA salt the titled compound (69.5 mg) as a pale yellow solid in 31%yield. [α]_(D)+23 (c 6.4, CH₂Cl₂); LCMS (M+H)⁺ 542.25; ¹H NMR (CDCl₃) δ7.71 (d, 2H, J=8.0), 7.50 (d, 2H, J=8.0), 7.16 (d, 1H, J=12.0), 7.05 (d,1H, J=8.0), 6.87 (t, 1H, J=8.0), 6.38 (br s, 1H), 5.91 (br s, 1H), 4.41(ABq, 2H, J=16, J_(ab)=176), 4.45 (m, 2H), 4.27 (t, 1H, J=8.0), 4.03 (m,4H), 3.70 (m, 2H), 3.51 (m, 2H), 3.10 (m, 2H), 1.83 (m, 1H), 1.29 (m,1H), 1.05 (m, 1H), 0.75 (d, 3H, J=8.0), 0.68 (d, 3H, J=8.0).Exemplification of Reaction Scheme 12

(2R)-2-{N-(4-Chlorobenzenesulfonyl)-N-[4-(1-hydroxy-1-methyl-ethyl)-benzyl]-amino}-4-methyl-pentanoicacid amide (Example 287)

A solution of the compound of Example 61[4-{[N-((1R)-1-carbamoyl-3-methyl-butyl)-N-(4-chlorobenzenesulfonyl)amino]-methyl}-benzoicacid methyl ester, 101 mg, 0.221 mmol] was cooled to 0° C. in THF (2mL). A solution of methyl magnesium bromide (1.4 M in toluene/THF, 0.50mL, 0.71 mmol) was added dropwise. The dark yellow solution was stirredat 0° C., and after 30 min, additional methyl magnesium bromide solution(0.25 mL, 0.353 mmol) was added. After 1 h, the solution was allowed towarm to rt. After 3.5 h, the reaction was quenched by the addition ofsat. aq. NH₄Cl, and the mixture was extracted with EtOAc (2×). Thecombined organic layers were dried (Na₂SO₄) and concentrated. Flashcolumn chromatography (SiO₂, 20 to 100% EtOAc/hexanes) provided thetitle compound as a white foam (62 mg, 62%). MS (ESI), (M+H)⁺ 453.16; ¹HNMR (CDCl₃, 300 MHz) δ 7.61 (d, 2H, J=8.7), 7.40 (d, 2H, J=8.7), 7.37(d, 2H, J=8.4), 7.26 (d, 2H, J=8.4), 6.28 (br s, 1H), 5.25 (br s, 1H),4.49 (d, 1H, J=15.9), 4.41 (d, 1H, J=15.9), 4.33 (t, 1H, J=6.6),1.73-1.80 (m, 1H), 1.55 (s, 6H), 1-28-1.35 (m, 1H), 1.20-1.25 (m, 1H),0.77 (d, 3H, J=6.5), 0.66 (d, 3H, J=6.6).Exemplification of Reaction Scheme 13

(2R)-2-{N-(4-Chlorobenzenesulfonyl)-[4-(5-methyl-[1, 3,4]oxadiazol-2-yl)-benzyl]-amino}-4-methyl-pentanoic acid amide (Example436)

Step 1: A solution of the compound of Example 61[4-{[N-((1R)-1-carbamoyl-3-methyl-butyl)-N-(4-chlorobenzenesulfonyl)amino]-methyl}-benzoicacid methyl ester, 0.500 g, 1.10 mmol] was diluted with methanol (10 mL)and hydrazine (2 mL) was added. The starting material slowly dissolvedover 5 min. After 30 min, the solution was heated at reflux. After 22 h,the solution was cooled to rt. Water (15 mL) was added, and a whiteprecipitate formed. The mixture was extracted with EtOAc (2×). Thecombined organic layers were washed with brine, dried (Na₂SO₄), andconcentrated to give the corresponding acyl hydrazide as a white foam,which was carried directly on to the cyclization step withoutpurification.

Step 2: The crude acyl hydrazide (0.150 g, 0.331 mmol) was dissolved inpyridine (2.2 mL) and ethyl acetimidate hydrochloride (60.0 mg, 0.364mmol) was added. The mixture was heated at reflux for 1.25 h. Thesolution was cooled to rt and concentrated to remove pyridine. Theresidue was taken up in EtOAc, and was washed sequentially with water, 1N HCl (2×), sat. aq. NaHCO₃, and brine. The solution was dried (MgSO₄)and concentrated. Flash column chromatography (SiO₂, 50 to 100%EtOAc/hexanes) provided the listed compound as a white solid (138 mg,88% for 2 steps). [α]_(D)+11.1 (c 7.0 mg/ml, CHCl₃); MS (ESI), (M+H)⁺477.22; ¹H NMR (CDCl₃, 300 MHz) δ 7.94 (dd, 2H, J=1.8, 8.4), 7.69 (dd,2H, J=1-8, 8.7), 7.45-7.50 (m, 4H), 6.23 (br s, 1H), 5.19 (br s, 1H),4.65 (d, 1H, J=15.9), 4.46 (d, 1H, J=15.9), 4.31 (dd, 1H, J=6.6, 7.8),2.61 (s, 3H), 1.75-1-85 (m, 1H), 1.28-1.35 (m, 1H), 1.08-1.15 (m, 1H),0.76 (d, 3H, J=6.6), 0.64 (d, 3H, J=6.6).Exemplification of Reaction Scheme 14

(2R)-2-{N-(4-Chlorobenzenesulfonyl)-N-[4-(3-methyl-[1, 2,4]oxadiazol-5-yl)-benzyl]-amino}-4-methyl-pentanoic acid amide (Example437)

Step 1: To a rt solution of the compound of Example 89[4-{[N-((1R)-1-carbamoyl-3-methyl-butyl)-N-(4-chlorobenzene-sulfonyl)-amino]-methyl}-benzoicacid, 520 mg, 1.2 mmol] in DMF (2.4 mL) and CH₂Cl₂ (7.1 mL) was added1-hydroxybenzotriazole (192 mg, 1.42 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (272 mg,1.42 mmol), and iPr₂NEt (0.31 mL, 1.8 mmol). N-Hydroxyacetamide (1.05mg, 1.42-mmol) was also added. After 21 h, starting material wasevident, so additional portions of all reagents were added periodicallyto push the reaction forward. After 3 d, the mixture was concentratedand partitioned between sat. aq. NaHCO₃ and EtOAc (2×). The combinedorganic layers were washed with brine, dried (MgSO₄), and concentratedto a yellow oil, which was carried on to the next step withoutpurification.

Step 2: The crude acetamidoxime was dissolved in toluene (10 mL) and thesolution was heated at reflux. After 1 h, pyridine (2 mL) was added andheating was continued for another 15 h. The mixture was concentrated anddiluted with EtOAc. The organic phase was washed sequentially withwater, 1 N HCl (2×), sat. aq. NaHCO₃, and brine, then was dried (MgSO₄)and concentrated. Flash column chromatography (SiO₂, 10 to 40%EtOAc/hexanes) gave the title compound as a pale yellow solid (238 mg,42% for two steps). [α]²³ _(D)+9.30 (c 5.93, CHCl₃); MS (ESI), (M+H)⁺477.18; ¹H NMR (CDCl₃, 300 MHz) δ 8.04 (d, 2H, J=8.4), 7.70 (dd, 2H,J=1.8, 8.4), 7.45-7.52 (m, 4H), 6.23 (br s, 1H), 5.19 (br s, 1H), 4.67(d, 1H, J=16.2), 4-47 (d, 1H, J=15.9), 4.31 (t, 1H, J=7.2), 2.47 (s,3H), 1.75-1.85 (m, 1H), 1.28-1.35 (m, 1H), 1.08-1.15 (m, 1H), 0-76 (d,3H, J=6.6), 0.64 (d, 3H, J=6.6).Exemplification of Reaction Scheme 15

(2R)-2-{N-(4-Chlorobenzenesulfonyl)-N-[4-(5-methyl-[1, 2,4]oxadiazol-3-yl)-benzyl]-amino}-4-methyl-pentanoic acid amide (Example465)

A solution of the compound of Example 6[(2R)-2-[N-(4-chlorobenzenesulfonyl)-N-(4-cyanobenzyl)amino]-4-methyl-pentanoicacid amide (0.20 g, 0.47 mmol) in ethanol (6 mL) was treated withhydroxylamine (50% solution in water, 0-050 mL, 0.71 mmol). The reactionwas heated to 80° C. for 18 h. The reaction was concentrated to aresidue and recrystallized from EtOAc/hexanes to produce a white solid(136 mg, 51%). This solid (0.18 mmol) was then dissolved in chloroformand treated with Et₃N (0.030 mL, 0-24 mmol) and acetyl chloride (0.020mL, 0.18 mmol). The reaction was stirred at rt for 2 h and then waspoured into EtOAc and brine. The organic layer was separated, dried overMgSO₄, and concentrated to residue. The residue was taken up in tolueneand heated at reflux for 24 h. The reaction was concentrated to aresidue and purified on a Biotage system (eluted in 1:1 EtOAc/hexanes)to afford the desired product as a white solid (35 mg, 39% yield). MS(ESI), (M+H)⁺ 477.13; ¹H NMR (CDCl₃, 500 MHz) δ 7.98 (d, 2H, J=8.2),7.68 (d, 2H, J=8.9), 7.45 (d, 4H, J=8.5), 6.21 (s, 1H), 5.19 (s, 1H),4.62 (d, 1H, J=15), 4.48 (d, 1H, J=16), 4.31 (t, 1H, J=7.0), 2.65 (s,3H), 1.75-1-85 (m, 1H), 1.20-1.35 (m, 4H), 1.10-1.17 (m, 1H), 0.85-0.90(m, 1H), 0.75 (d, 3H, J=6.7), 0.64 (d, 3H, J=6.4).Exemplification of Reaction Scheme 16

(2R)-2-[N-(4-Acetylbenzyl)-N-(4-chlorobenzenesulfonyl)amino]-4-methyl-pentanoicacid amide (Example 273)

A solution of the compound of Example 251[4-{[N-((1S)-1-carbamoyl-3-methyl-butyl)-N-(4-chlorobenzenesulfonyl)-amino]-methyl}-N-methoxy-N-methyl-benzamide,0.100 g, 0.207 mmol] was cooled to 0° C. in THF (2.1 mL). A solution ofmethyl magnesium bromide (1.4 M in toluene/THF, 0.178 mL, 0.249 mmol)was added dropwise. The resulting solution was stirred at 0° C. for 3 h,at which time additional methyl magnesium bromide solution (0.178 mL,0.249 mmol) was added. After another 30 min, a final portion of MeMgBrsolution (0.3 mL) was added. After a final 15 min, the reaction wasquenched by the addition of sat. aq. NH₄Cl and 1 N HCl, and the mixturewas extracted with EtOAc (2×). The combined organic layers were washedwith sat. aq. NaHCO₃ and brine, dried (Na₂SO₄) and concentrated. Flashcolumn chromatography (SiO₂, 20 to 60% EtOAc/hexanes) gave the desiredcompound as an off-white foam (79 mg, 87%). [α]²³ _(D)+20.4 (c 7.57,CHCl₃); MS (ESI), (M+H)⁺ 437.13; ¹H NMR (CDCl₃, 300 MHz) δ 7.87 (d, 2H,J=8.4), 7.67 (dd, 2H, J=1.8, 8.7), 7.42-7.46 (m, 4H), 6.21 (br s, 1H),5.28 (br s, 1H), 4.64 (d, 1H, J=15.9), 4.45 (d, 1H, J=15.9), 4.31 (t,1H, J=6.6), 2.58 (s, 3H), 1.73-1.80 (m, 1H), 1.25-1.35 (m, 1H),1.05-1.14 (m, 1H), 0.74 (d, 3H, J=6.5), 0.65 (d, 3H, J=6.6).Exemplification of Reaction Scheme 17

(2R)-2-{N-(4-Chlorobenzenesulfonyl)-N-[4-(3-piperidin-1-yl-propionylamino)-benzyl]-amino}-4-methyl-pentanoicacid amide (Example 274)

To a solution ofN-(4-{[N-((1S)-1-carbamoyl-3-methyl-butyl)-N-(4-chlorobenzenesulfonyl)amino]-methyl}-phenyl)-acrylamide(0.10 g, 0.22 mmol) in toluene (5 mL) was added piperidine (20 mg, 0.24mmol). The mixture was heated at a gentle reflux for 1 h and then thesolvent was removed in vacuo. Purification by flash chromatography(SiO₂, 10% MeOH/CH₂Cl₂) afforded the title compound (105 mg) in 86%yield. MS (ESI), (M+H)⁺ 449.16, ¹H NMR (CDCl₃, 400 MHz) δ 7.69 (d, 2H,J=8.0), 7.63 (d, 2H, J=8.0), 7.38 (d, 2H, J=8.0), 7.23 (d, 2H, J=8.0),6.25 (br s, 1H), 5.35 (br s, 1H), 4.75 (d, 1H, J_(ab)=16), 4.38 (d, ¹H,J_(ab)=16), 3-25 (t, 1H, J=6.0), 2.65 (t, 2H, J=6.0), 2.56-2.44 (m, 6H),1.95 (m, 1H), 1.68-1.45 (m, 8H), 0.98 (d, 3H, J=7.0), 0.94 (d, 3H,J=7.0)Exemplification of Reaction Scheme 18

(2R)-2-(Benzhydrylidene-amino)-1-{(1′S),(5′S)-10′,10′-dimethyl-3′,3′-dioxo-3′λ⁶-thia-4′-aza-tricyclo-[5.2.1.0^(1,5)]dec-4′-yl}-4-fluorobutan-1-one

To a −78° C. solution ofN-2-(benzhydrylidene-amino)-1-{(1′S),(5′S)-10′,10′-dimethyl-3′,3′-dioxo-3′λ⁶-thia-4′-aza-tricyclo-[5.2.1.0^(1,5)]dec-4′-yl}ethanone(ref: Josien, H.; Martin, A.; Chassaing, G. Tetrahedron Lett. 1991, 32,6547; 30.0 g, 68 mmol) in HMPA (60 mL) and THF (300 mL) was added n-BuLi(1.6 M in hexane, 42.4 mL, 68 mmol) dropwise, maintaining thetemperature below −65° C. The reaction was allowed to come to rt, atwhich time a solution of 1-bromo-3-fluoroethane (17.4 g, 137 mmol) inTHF (30 mL) was added dropwise at rt. After 18 h the reaction was pouredover H₂O/HOAc (200 mL/2 mL), diluted with EtOAc, and the organic layerswere washed with saturated NH₄Cl, brine, dried over MgSO₄, andconcentrated. The resulting orange oil was then further purified bysilica gel chromatography (25% EtOAc/hexanes) to afford a white solidwhich was recrystallized from 15% EtOAc/hexanes to give the desiredmaterial (24.3 g, 70%). MS (ESI) (M+H⁺) 483.27; ¹H NMR (CDCl₃) δ 7.66(d, 2H, J=7.2), 7.13-7.44 (m, 8H), 4.82-4.83 (m, 2H), 4.39-4.81 (m, 2H),3.84-3.87 (m, 1H), 3.28 (ABq, 2H, J=18, 10) 2.33-2.41 (m, 2H), 2.02-2.04(m, 2H), 1.84-1.87 (m, 2H), 1.32-1.39 (m, 2H), 1.10 (s, 3H), 0.91 (s,3H).

(2R)-2-Amino-1-{(1′S),(5′S)-10′,10′-dimethyl-3′,3′-dioxo-3′λ⁶-thia-4′-aza-tricyclo-[5.2.1.0^(1,5)]dec-4′-yl}-4-fluorobutan-1-one

A solution of(2R)-2-(benzhydrylidene-amino)-1-{(1′S),(5′S)-1′,10′-dimethyl-3′,3′-dioxo-3′λ₆-thia-4′-aza-tricyclo-[5.2.1.0^(1,5)]dec-4′-yl}-4-fluorobutan-1-one(20.0 g, 41.0 mmol) in THF (400 mL) was treated with 1 N HCl (200-mL).After 3 h, the reaction was diluted with H₂O and extracted with Et₂O.The aqueous phase was then neutralized by the addition of 0.5 N NaOH.The basic phase was then extracted with CH₂Cl₂, dried over MgSO₄, andconcentrated to give a white solid (11.9 g, 90%). ¹H NMR (CDCl₃) δ4.56-4.71 (m, 2H), 4.23-4.31 (m, 1H), 3.40-3.49 (m, 3H), 3.11 (d, 2H,J=4.4), 1.17-2.23 (m, 8H), 1.13 (s, 3H), 0.93-1.12 (m, 3H).

(2R)-2-(4-Chlorobenzensulfonylamino)-1-{(1′S),(5′S)-10′,10′-dimethyl-3′,3′-dioxo-3′λ⁶-thia-4′-aza-tricyclo-[5.2.1.0^(1,5)]dec-4′-yl}-4-fluorobutan-1-one

To a solution of(2R)-2-amino-1-{(1′S),(5′S)-10′,10′-dimethyl-3′,3′-dioxo-3′λ⁶-thia-4′-aza-tricyclo-[5.2.1.0^(1,5)]dec-4′-yl}-4-fluorobutan-1-one:(12 g, 36 mmol) and Et₃N (10.4 mL, 72.0 mmol) in CH₂Cl₂ (350 mL) wasadded 4-chlorobenzenesulfonyl chloride (9.1 g, 43 mmol) in one portion.After 18 h the reaction was concentrated and the resulting residue wastaken into EtOAc and washed with H₂O, brine, dried over MgSO₄, andconcentrated. The material was then further purified by silica gelchromatography (30% EtOAc/hexanes) to afford the titled compound (16.0g, 92%) as a white wax. ¹H NMR (CDCl₃) δ 7.79 (d, 2H, J=8.0), 7.43 (d,2H, J=8.0), 5.69 (br d, 8.0), 4.42-4.77 (m, 4H), 3.71-3.72 (m, 1H), 3.10(ABq, 2H, J=9, 4.4) 2.11-2.29 (m, 2H), 1.33-1.99 (m, 6H), 1.04 (s, 3H),0.91 (s, 3H).

(2R)-2-(4-Chlorobenzenesulfonylamino)-4-fluorobutanoic acid

To a rapidly stirred solution of(2R)-2-(4-chlorobenzensulfononylamino)-1-{(1′S),(5′S)-10′,10′-dimethyl-3′,3′-dioxo-3′λ⁶-thia-4′-aza-tricyclo-[5.2.1.0^(1,5)]dec-4′-yl}-4-fluorobutan-1-one:(16 g, 32 mmol) in acetonitrile (200 mL) was added LiBr (13.9 g, 16mmol), tetrabutylammonium bromide (4.13 g, 12.8 mmol), and LiOH (5.45 g,0.130 mol). After 4.5 h the reaction was concentrated to half volumethen diluted with H₂O and extracted with CH₂Cl₂. The aqueous layer wasacidified with 1 N HCl and extracted with EtOAc. The EtOAc extracts werecombined, dried over MgSO₄, and concentrated to give a white solid ofwhich 9.4 g was taken directly towards the next step. ¹H NMR (DMSO-d₆) δ8.39 (d, 1H, J=9.0), 7.76 (d, 2H, J=6.8), 7.64 (d, 2H, J=6.8), 7.00 (brs, 1H), 4.29-4.48 (m, 2H), 3.80-3.88 (m, 1H), 1.66-1.96 (m, 2H).

(2R)-2-(4-Chlorobenzenesulfonylamino)-4-fluorobutanoic acid amide

To a solution of (2R)-2-(4-chlorobenzenesulfonylamino)-4-fluorobutanoicacid (9.0 g, 31 mmol) in DMF (250 mL) was added consecutively1-hydroxybenzotriazole hydrate (6.2 g, 46 mmol),N,N-diisopropylethylamine (23 mL, 124 mmol), ammonium chloride (3.34 g,62 mmol), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimidehydrochloride (8.8 g, 46 mmol) under N₂. The resulting solution wasstirred at rt for 18 h. The solution was poured over ice water (500 mL)and the solid was filtered off and dried. The material was thenprecipitated from 10% EtOAc/hexanes to afford a clean white solid (4.5g) in 50% yield. [α]_(D)=−21.0 (c 1.00, DMF); MS (ESI) (M−H⁻) 293.01; ¹HNMR (DMSO-d₆) δ 8.12 (d, 1H, J=8.8), 7.77 (d, 2H, J=7.0), 7.62 (d, 2H,J=7.0), 7.38 (br s, 1H), 7.03 (br s, 1H), 4.22-4.47 (m, 2H), 3.71-3-85(m, 1H), 1.65-1.92 (m, 2H).

(2R)-2-[(4-Chlorobenzenesulfonyl)-(4-cyanobenzyl)-amino]-4-fluorobutyramide(Example 360)

(2R)-2-(4-Chlorobenzenesulfonylamino)-4-fluorobutyramide (20 mg, 0.7mmol) was converted to the title compound as in Reaction Scheme 1,method A to afford the titled compound (208 mg) in 73% yield. MS (ESI)(M−H)⁻ 407.99; [α]_(D)=+39.13 (c 1.00, MeOH); ¹H NMR (CDCl₃) δ 7.72 (d,2H, J=8.4) 7.58 (d, 2H, J=8.4), 7.50 (d, 2H, J=8.4), 7.45 (d, 2H,J=8.4), 6.29 (br s, 1H), 5.21 (br s, 1H), 4.19-4.67 (m, 5H), 2.17-2.28(m, 1H), 1.49-1.61 (m, 1H).Exemplification of Reaction Scheme 19

2-(4-Chlorobenzenesulfonylamino)-6-fluoro-hexanoic acid amide (III)

A mixture of (benzhydrylidene-amino)acetic acid ethyl ester (8.6 g, 32mmol), 4-bromo-1-fluorobutane (10.0 g, 64.5 mmol), K₂CO₃ (13.4 g, 96.9mmol), tetrabutylammonium bromide (2.1 g, 6.5 mmol), and acetonitrile(300 mL) was heated at reflux for 72 h. The reaction was cooled to rtand filtered through a sintered glass funnel. The filtrate wasconcentrated in vacuo. The residue was dissolved in diethyl ether (250mL) and a white solid precipitated. The solid was removed by vacuumfiltration. A solution of 1 N HCl (100 mL) was added to the filtrate,which contained the crude product(2-(benzhydrylideneamino)-6-fluorohexanoic acid ethyl ester). Theresulting biphasic mixture was stirred vigorously for 3 h. The mixturewas transferred to a separatory funnel. The aqueous layer was collected.The organic layer was extracted with 1 N HCl (30 mL). The combinedaqueous layers were washed with 200 mL of diethyl ether. ConcentratedHCl (10.8 mL) was added to the aqueous portion and the resultingsolution was heated at reflux for 6 h. The reaction mixture was cooledto rt and concentrated in vacuo. Toluene was added to the residue andthe mixture was reconcentrated in vacuo to afford2-amino-6-fluoro-hexanoic acid hydrochloride as a white solid. The crudeamino acid salt was used without purification or characterization.2-Amino-6-fluorohexanoic acid hydrochloride (32.3 mmol, theoretically)was suspended in anhydrous methanol (300 mL) and cooled to 0° C. Thionylchloride (10.3 mL, 129 mmol) was slowly was over 5 min. The resultingsolution was allowed to warm to rt and stir for 18 h. The reactionmixture was concentrated in vacuo to afford methyl2-amino-6-fluoro-hexanoic acid hydrochloride. Toluene (100 mL) and 28%ammonia in water (75 mL) were added to the crude amino ester. Theresulting biphasic mixture was stirred vigorously at rt for 24 h. Thereaction mixture was concentrated in vacuo. The residual solid wassuspended in toluene (200 mL) and reconcentrated in vacuo to afford6-fluorohexanoic acid amide (II) as a white solid. The crude amino acidamide was dissolved in anhydrous DMF (50 mL) and CH₂Cl₂ (350 mL) andreacted with 4-chlorobenzenesulfonylchloride (82 g, 32.3 mmol) and Et₃N(13.5 mL, 96.9 mmol). After 2 h, a second portion of4-chlorobenzenesulfonylchloride (1.70 g, 8.1 mmol) was added. After anadditional 18 h, the resulting mixture was poured into 1 N HCl (500 mL).The organic layer was collected and washed with water (2×500 mL). Hexane(600 mL) was added to the organic layer. A white precipitate formed. Thesolid was collected by vacuum filtration, rinsed with cold ethanol (50mL), and dried in vacuo to afford 4.95 g (48% yield, 6 steps) of2-(4-chlorobenzenesulfonylamino)-6-fluoro-hexanoic acid amide (III):LCMS (M+Na)⁺ 345.2; ¹H NMR (400 MHz, DMSO-d₆) 7.99 (d, 1H, J=8.8), 7.77(d, 2H, J=8.8), 7.62 (d, 2H, J=8.8), 7.29 (s, 1H), 6.95 (s, 1H), 4.34(dt, 2H, J_(d)=47.5, J_(t)=6.1), 3.65 (dt, 1H, J_(d)=5.6, J_(t)=8.6),1.60-1.39 (m, 4H), 1.36-1.15 (m, 2H); Anal. Calcd for C₁₂H₁₆ClFN₂O₃S: C,44.65; H, 4.99; N, 8.67. Found: C, 44.61; H, 5.08; N, 8.75.

2-[(4-Chlorobenzenesulfonyl)-(4-cyanobenzyl)-amino]-6-fluoro-hexanoicacid amide (Example 333)

2-(4-Chlorobenzenesulfonylamino)-6-fluoro-hexanoic acid amide (0.500 g,1.55 mmol) was converted to the title compound (360 mg, 50% yield) as inReaction Scheme 1, method A. LCMS (M+Na)⁺ 459.9; ¹H NMR (400 MHz,DMSO-d₆) δ 7.82 (d, 2H, J=8.8), 7.79 (d, 2H, J=8.5), 7.63 (d, 2H,J=8.8), 7.58 (d, 2H, J=8-3), 7.52 (s, 1H), 7.09 (s, 1H). 4.82 (ABq, 2H,Δν=37.2, J_(ab)=17.6), 4.34 (dd, 1H, J=8.0, 6.6), 4.25 (dt, 2H,J_(d)=47.2, J_(t)=5.7), 1.58(m, 1H), 1.49-1.12 (m, 5H); Anal. Calcd forC₂₀H₂₁ClFN₃O₃S: C, 54.85; H, 4.83; N, 9.59. Found: C, 54.92; H, 4.76; N,9.54.Exemplification of Reaction Scheme 20

(2R)-2-(4-Chlorobenzensulfonylamino)-1-{(1′S),(5′S)-10′,10′-dimethyl-3′,3′-dioxo-3′λ⁶-thia-4′-aza-tricyclo-[5.2.1.0^(1,5)]dec-4′-yl}-4-fluoro-4-methyl-pentan-1-one

To a solution of(2R)-2-(4-chlorobenzensulfonylamino)-1-{(1′S),(5′S)-10′,10′-dimethyl-3′,3′-dioxo-3′λ⁶-thia-4′-aza-tricyclo-[5.2.1.0^(1,5)]dec-4′-yl}-4-methyl-4-penten-1-one[500 mg, 1 mmol, prepared as in Reaction Scheme 18 fromN-2-(benzhydrylidene-amino)-1-{(1′),(5′S)-10′,10′-dimethyl-3′,3′-dioxo-3λ⁶-thia-4′-aza-tricyclo-[5.2.1.0^(1,5)]dec-4′-yl}ethanone(ref: Josien, H.; Martin, A.; Chassaing, G. Tetrahedron Lett. 1991, 32,6547) and 1-bromo-2-methyl-2-propene] in THF (5 mL) at 0° C. was addedhydrofluoric acid.pyridine (10 mL). The reaction mixture was allowed towarm to rt and stir for 18 h. The reaction contents were carefully addedto a saturated aqueous solution of NaHCO₃ (300 mL). The aqueous mixturewas extracted with EtOAc (3×100 mL). The combined organic layers weresequentially washed with 1 N HCl (200 mL) and brine (100 mL). Theorganic layer was dried over MgSO₄, filtered, and concentrated in vacuoto afford 490 mg (94%) of the title compound as a white solid: ¹H NMR(400 MHz, DMSO-d₆) δ 7.83 (d, 2H, J=8.8), 7.45 (d, 2H, J=8.8), 5.37 (d,1H, J=8.1), 4.65 (m, 1H), 3-64 (t, 1H, J=6.4), 3.43 (ABq, 2H, Δν=5.4,J_(ab)=13.7), 2.19-1.83 (m, 7H), 1.41-1.31 (m, 8H), 1.04 (s, 3H), 0.94(s, 3H).

(2R)-2-(4-Chlorobenzenesulfonylamino)-4-fluoro-4-methyl-pentanoic acidamide

(2R)-2-(4-Chlorobenzensulfonylamino)-1-{(1′S),(5′S)-10′,10′-dimethyl-3′,3′-dioxo-3′λ⁶-thia-4′-aza-tricyclo-[5.2.1.0^(1,5)]dec-4′-yl}-4-fluoro-4-methyl-pentan-1-onewas converted to the title compound in two steps as in Reaction Scheme18 (165 mg, 55% yield): LCMS (M+Na)⁺ 345.1; ¹H NMR (500 MHz, DMSO-d₆) δ8.10 (d, 1H, J=9.2), 7.77 (d, 2H, J=8.5), 7.62 (d, 2H, J=8.9), 7.34 (s,1H), 6.92 (s, 1H). 3.85 (m, 1H), 1.89 (m, 1H), 1.74 (m, 1H), 1.31 (d,3H, J=21.7), 1.29 (d, 3H, J=21.9).Exemplification of Reaction Scheme 21

Ethyl 2-(4-chlorobenzenesulfonylamino)-4-methyl-4-pentenoate

A solution of ethyl 2-amino-4-methyl-4-pentenoate (2.84 g, 18.1 mmol,prepared as in Reaction Scheme 19 from (benzhydrylideneamino)acetic acidethyl ester and 1-bromo-2-methyl-2-propene) in CH₂Cl₂ (250 mL) wasreacted with 4-chlorobenzenesulfonyl chloride (4.20 g, 19.9 mmol) andEt₃N (3.78 mL, 27.2 mmol). After 4 h, the resulting mixture was pouredinto 1 N aqueous HCl (500 mL) and extracted with EtOAc (3×150 mL). Theorganic layer was washed with brine (50 mL), dried (MgSO₄), filtered,and concentrated in vacuo. The crude concentrate was purified usingsilica gel column chromatography (10:1 to 5:1 gradient, hexanes/EtOAc)to afford 3.04 g (25% yield over 3 steps) of ethyl2-(4-chlorobenzenesulfonylamino)-4-methyl-4-pentenoate: LCMS (M+Na)⁺354.2; ¹H NMR (400 MHz, CDCl₃) 7.77 (d, 2H, J=9.1), 7.46 (d, 2H, J=8.8),5.07 (d, 1H, J=9.0), 4.84 (s, 1H), 4.73 (s, 1H), 4.05 (m, 1H), 3.95 (q,2H, J=7.1), 2.40 (m, 2H), 1.66 (s, 3H), 1.13 (t, 3H, J=7.1).

2-(4-Chlorobenzenesulfonylamino)-4-fluoro-4-methyl-pentanoic acid ethylester and4-Chloro-N-(5,5-dimethyl-2-oxo-tetrahydro-furan-3-yl)-benzenesulfonamide

Hydrogen fluoride.pyridine (10 mL) was added to a 0° C. solution ofethyl 2-(4-chloro-benzenesulfonylamino)-4-methyl-4-pentenoate (1.0 g,3.0 mmol) in THF (15 mL). The reaction mixture was allowed to warm tort. After 5 h, an additional portion (10 mL) of hydrogenfluoride-pyridine was added. The mixture was stirred for 24 h, then athird portion of hydrogen fluoride-pyridine (10 mL) was added. After atotal of 53 h, the reaction was quenched with ice chips (20 mL). Thecrude mixture was poured into ice water (500 mL) and extracted withCH₂Cl₂ (2×200 mL). The combined organic layers were washed with sat. aq.NaHCO₃ (100 mL) and concentrated in vacuo. The crude concentrate waspurified using silica gel column chromatography (10:1 to 5:1 gradient,hexanes/EtOAc) to afford 0.395 g (37% yield) of ethyl2-(4-chlorobenzenesulfonylamino)-4-fluoro-4-methyl-pentanoate and 0.425g (46% yield) of4-chloro-N-(5,5-dimethyl-2-oxo-tetrahydro-furan-3-y)-benzenesulfonamide.Data for ethyl2-(4-chlorobenzenesulfonylamino)-4-fluoro-4-methyl-pentanoate: LCMS(M+Na)⁺ 374.1; ¹H NMR (500 MHz, CDCl₃) 7.78 (d, 2H, J=8.9), 7.47 (d, 2H,J=8.5), 5.19 (d, 1H, J=7.9), 4.08 (m, 1H), 3.93 (m, 2H), 2.09-1.94 (m,2H), 1.42 (d, 3H, J=21.6), 1.37 (d, 3H, J=21.6), 1.12 (t, 3H, J=7.0).Data for4-chloro-N-(5,5-dimethyl-2-oxo-tetrahydro-furan-3-yl)-benzenesulfonamide:LCMS (M+Na)⁺ 326.0; ¹H NMR (400 MHz, DMSO-d₆) 8.41 (d, 1H, J=9.1), 7.86(d, 2H, J=8.6), 7.67 (d, 2H, J=8.8), 4.57 (m, 1H), 2.22 (dd, 1H, J=12.4,9.0), 1.72 (t, 1H, J=12.0), 1.33 (s, 3H), 1.31 (s, 3H).

2-(4-Chlorobenzenesulfonylamino)-4-fluoro-4-methyl-pentanoic acid amide

A solution of2-(4-chlorobenzenesulfonylamino)-4-fluoro-4-methyl-pentanoic acid ethylester (457 mg, 1.30 mmol) in MeOH (20 mL) was treated with 10 N NaOH(780 μL, 7.8 mmol) at rt for 18 h. The crude reaction mixture wasconcentrated in vacuo. The residue was treated with water (50 mL) and 1N HCl (20 mL). The aqueous solution was extracted with EtOAc (3×100 mL).The combined organic layers were washed with brine (50 mL), dried overMgSO₄, filtered and concentrated in vacuo to afford a white solidcontaining 2-(4-chlorobenzenesulfonylamino)-4-fluoro-4-methyl-pentanoicacid. A mixture of the crude solid, 1-hydroxybenzotriazole (263 mg, 1.95mmol), diisopropylethylamine (670 mg, 5.2 mmol), ammonium chloride (140mg, 2.6 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (373 mg, 1.95 mmol), and DMF (20 mL) was stirred at rt for24 h. The crude mixture was poured into water (500 mL). The aqueoussolution was extracted with EtOAc/hexane (90:10, 3×150 mL). The combinedorganic layers were washed with brine (50 mL), dried over MgSO₄,filtered and concentrated in vacuo. The crude concentrate was purifiedusing silica gel column chromatography (95:5, chloroform/MeOH) to afford0.426 g (100% yield) of the title compound: LCMS (M+Na)⁺ 345.3; ¹H NMR(400 MHz, DMSO-d₆) δ 8.0(0 (d, 1H, J=9.2), 7.77 (d, 2H, J=8.5), 7.62 (d,2H, J=8.9), 7.34 (s, 1H), 6.92 (s, 1H). 3.85 (m, 1H), 1.89 (m, 1H), 1.74(m, 1H), 1.31 (d, 3H, J=21.7), 1.29 (d, 3H, J=21.9).

2-[(4-Chlorobenzenesulfonyl)-(4-cyanobenzyl)-amino]-4-fluoro-4-methyl-pentanoicacid amide (Example 357)

2-(4-Chlorobenzenesulfonylamino)-4-fluoro-4-methyl-pentanoic acid amidewas converted to the title compound as in Reaction Scheme 1, method A.LCMS (M+Na)⁺ 460.2; ¹H NMR (400 MHz, DMSO-d₆) δ 7.83 (d, 2H, J=8.5),7.75 (d, 2H, J=8.3), 7.68 (s, 1H), 7.64 (d, 2H, J=8.6), 7.49 (d, 2H,J=8.1), 7.20 (s, 1H), 4.67 (ABq, 2H, Δν=28.3, J_(ab)=17.3), 4.54 (dd,1H, J=9.3, 3.2), 2.23 (m, 1H), 1.42 (m, 1H), 1.25 (d, 3H, J=21.6), 1.21(d, 3H, J=21.7).

2-[(4-Chlorobenzenesulfonyl)-(4-cyanobenzyl)-amino]-4-hydroxy-4-methyl-pentanoicacid amide (Example 443)

A sealed vial containing a mixture of4-chloro-N-(5,5-dimethyl-2-oxo-tetrahydro-furan-3-yl)-benzenesulfonamide(0.20 g, 0.66 mmol) and 28% ammonia in water (3 mL) was heated in amicrowave reactor at 80° C. for 40 min. The reaction mixture was cooledto rt and concentrated to dryness in vacuo to afford a white solidcontaining 2-(4-chlorobenzenesulfonylamino)-4-hydroxy-4-methyl-pentanoicacid amide. The crude solid was converted to the title compound (98 mg,34% yield) as in Reaction Scheme 1, method A: LCMS (M+Na)⁺ 458.2; ¹H NMR(400 MHz, DMSO-d₆) δ 7.84 (d, 2H, J=8.6), 7.76 (d, 2H, J=8.3), 7.62 (d,2H, J=8.8), 7.51 (d, 2H, J=8.3), 7-40 (s, 1H), 7.11 (s, 1H), 4.63 (ABq,2H, Δν=5.9, J_(ab)=17.6), 4.56 (dd, 1H, J=8.3, 2.5), 4.54 (s, 1H), 1.95(dd, 1H, J=13.7, 8.6), 1.26 (dd, 1H, J=13.6, 2.4), 1.04 (s, 3H), 0.99(s, 3H). Anal. Calcd for C₂₀H₂₂ClN₃O₄S: C, 55.10; H, 5.08; N, 9.64.Found: C, 54.96; H, 5.14; N, 9.58.Exemplification of Reaction Scheme 22

2-(4-Chlorobenzenesulfonylamino)-5-hexenoic acid ethyl ester

A mixture of (benzhydrylidene-amino)acetic acid ethyl ester (20 g, 74.8mmol), 4-bromo-1-butene (10.1 g, 74.8 mmol), K₂CO₃ (31.0 g, 224 mmol),tetrabutylammonium bromide (2.41 g, 7.48 mmol), and acetonitrile (150mL) was heated at reflux for 6 h. The reaction was cooled to rt andfiltered through a sintered glass funnel. The filtrate was concentratedin vacuo. The residue was dissolved in diethyl ether (250 mL) and awhite solid precipitated. The solid was removed by vacuum filtration. Asolution of 1 N HCl (150 mL) was added to the filtrate, which containedthe crude product (2-(benzhydrylidene-amino)-hex-5-enoic acid ethylester). The resulting biphasic mixture was stirred vigorously for 18 h.The mixture was transferred to a separatory funnel. The aqueous layerwas collected and concentrated in vacuo. The residue was dissolved intoluene (2×200 mL) and reconcentrated. The crude amino ester wasdissolved in CH₂Cl₂ and reacted with 4-chlorobenzenesulfonyl chloride(15.8 g, 74.8 mmol) and Et₃N (31.2 mL, 224 mmol). After 18 h, theresulting mixture was poured into 1 N HCl (500 mL). The organic layerwas collected and washed sequentially with 1 N HCl (500 mL) and brine(50 mL). The organic layer was dried over MgSO₄, filtered, andconcentrated in vacuo. The crude concentrate was purified using silicagel column chromatography (5:1, hexanes/EtOAc) to afford 5.57 g (23%yield over 3 steps) of the title compound: LCMS (M+Na)⁺ 354.0; ¹H NMR(400 MHz, DMSO-d₆) δ 8.47 (d, 1H, J=8.8), 7.76 (d, 2H, J=8.8), 7.66 (d,2H, J=8.8), 5.69 (m, 1H), 4.95-4.88 (m, 2H). 3.86 (q, 2H, J=7.1), 3.76(m, 1H), 1.98 (m, 2H), 1.71-1.54 (m, 2H), 1.03 (t, 311, J=7.1).

2-[(4-Chlorobenzenesulfonyl)-(4-cyanobenzyl)-amino]-hex-5-enoic acidethyl ester

2-[(4-Chlorobenzenesulfonyl)-(4-cyanobenzyl)-amino]-hex-5-enoic acidethyl ester was made in a similar manner to Reaction Scheme 1 startingfrom 2-(4-chloro-benzenesulfonylamino)-hex-5-enoic acid ethyl ester.2-[(4-Chlorobenzenesulfonyl)-(4-cyanobenzyl)-amino]-hex-5-enoic acidethyl ester was isolated as a crude yellow solid (1.14 g) and used inthe next step without further purification. ¹H NMR (CDCl₃) δ 7.71 (d,2H, J=8.0), 7.61 (d, 2H, J=8.0), 7.53 (d, 2H, J=8.0), 7.46 (d, 2H,J=8.0), 5-54 (m, 2H), 4.90 (m, 2H), 4.74 (d, 1H, J=16.0), 4.48 (m, 2H),3.90 (m, 1H), 1.95 (m, 2H), 1.81 (m, 1H), 1.48 (m, 1H), 1.11 (t, 3H,J=8.0).

2-[(4-Chlorobenzenesulfonyl)-(4-cyanobenzyl)-amino]-5-oxo-pentanoic acidethyl ester

A mixture of(4-chlorobenzenesulfonyl)-(4-cyanobenzyl)-amino]-hex-5-enoic acid ethylester (1.14 g, 2.56 mmol), osmium tetraoxide (0.03(0 g, 0.13 mmol), andtrimethylamine N-oxide (0.41 g, 5.5 mmol) was dissolved in acetone (50mL) and stirred for 4 h at rt. Upon completion, the solution wasconcentrated in vacuo and redissolved in 1.5:1 dioxane:H₂O (50 mL). Tothis solution, sodium periodate (0.66 g, 3-07 mmol) was added andstirred at rt for 18 h. The reaction was then diluted with EtOAc (500mL) and washed with H₂O, brine, dried over Na₂SO₄ and concentrated togive a crude colorless oil. Further purification by flash chromatography(SiO₂, 5 to 75% EtOAc/hexanes) afforded2-[(4-chlorobenzenesulfonyl)-(4-cyanobenzyl)-amino]-5-oxo-pentanoic acidethyl ester (0.26 g) as a colorless oil in 23% yield. ¹H NMR (CDCl₃) δ9.57 (s, 1H), 7.69 (d, 2H, J=8.0), 7.51 (m, 6H), 5.99 ABq, 2H, Δv=16,J_(ab)=168), 4.47 (m, 1H), 3.89 (m, 2H), 2.53 (m, 1H), 2.32 (m, 1H),2.11 (m, 1H), 1.61 (m, 1H), 1.06 (t, 3H, J=8.0).

2-[(4-Chlorobenzenesulfonyl)-(4-cyanobenzyl)-amino]-5,5-difluoro-pentanoicacid ethyl ester

2-[(4-Chlorobenzenesulfonyl)-(4-cyanobenzyl)-amino]-5-oxo-pentanoic acidethyl ester (0.05 g, 0.11 mmol) was slowly added to a solution of DAST(0.020 mL, 0.11 mmol) in CH₂Cl₂ (2 mL) at rt and stirred for 16 h. Thereaction was diluted with CH₂Cl₂ (20 mL) and extracted with H₂O (2×25mL). The combined organic layers were washed with H₂O, brine, dried overNASO₄ and concentrated to give2-[(4-Chloro-benzenesulfonyl)-(4-cyanobenzyl)-amino]-5,5-difluoro-pentanoicacid ethyl ester as a crude yellow residue (61 mg). This crude residuewas taken onto the next step without further purification.

2-[(4-Chlorobenzenesulfonyl)-(4-cyanobenzyl)-amino]-5,5-difluoro-pentanoicacid amide (Example 377)

The crude2-[(4-chlorobenzenesulfonyl)-(4-cyanobenzyl)-amino]-5,5-difluoro-pentanoicacid ethyl ester (0.061 g, 0.13 mmol) was dissolved in MeOH (2 mL). Tothis mixture was added 10 N NaOH (0.052 mL, 0.52 mmol) and the resultingsolution was stirred at rt for 16 h. The reaction was diluted with H₂O(25 mL), acidified with 1 N HCl, and extracted with CH₂Cl₂ (4×100 mL).The combined organic layers were dried over Na₂SO₄ and concentrated invacuo to give the carboxylic acid moiety as a crude colorless oil. Thecarboxylic acid intermediate was then dissolved in DMF (10 mL) and mixedwith 1-hydroxybenizotriazole (0.030 g, 0.20 mmol), iPr₂NEt (0.090 mL,0.52 mmol), NH₄Cl (0.01 g, 0.26 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.04 g,0.20 mmol) and stirred at rt for 72 h. The reaction was diluted withEtOAc (150 mL) and washed with H₂O (4×50 mL). The organic layer wasdried over Na₂SO₄ and concentrated in vacuo to give a crude off-whitesolid. Further purification by flash chromatography (SiO₂, 5 to 85%EtOAc/hexanes) afforded the titled compound (10.7 mg) as a white solidin 19% yield. LCMS (M+Na)⁺ 464.01; ¹H NMR (CDCl₃) δ 7.69 (d, 2H, J=8.3),7.60 (d, 2H, J=8.3), 7.49 (m, 4H), 6.18 (br s, 1H), 5.67 (tt, 1H, J=56,4.0), 5.22 (br s, 1H), 4.52 (ABq, 2H, Δν=16, J_(ab)=100), 4.34 (m, 1H),2.03 (m, 1H), 1.68 (m, 1H), 1.38 (m, 1H), 0.86 (m, 1H).Exemplification of Reaction Scheme 23

(2R)-2-[[4-(2-Bromo-acetylamino)-benzyl]-(4-chlorobenzenesulfonyl)-amino]-4-methyl-pentanoicacid amide

To a solution of(2R)-2-[(4-aminobenzyl)-(4-chloro-benzenesulfonyl)amino]-4-methyl-pentanoicacid amide (248 mg, 0.56 mmol) and Et₃N (176 mg, 1.74 mmol) in CH₂Cl₂ (3mL) was added bromoacetylchloride (105 mg, 0.67 mmol). The reactionmixture was stirred overnight at rt. The reaction mixture was dilutedwith CH₂Cl₂ (5 mL), washed with 1 N HCl, brine, and dried through acotton plug. The solvent was removed in vacuo. Purification by flashchromatography (SiO₂, 10% acetone/CH₂Cl₂) afforded the title compound(124 mg) in 42% yield. MS (ESI), (M+H)⁺ 531.86, ¹H NMR (CDCl₃, 400 MHz)δ 8.78 (br s, NH), 7.95 (d, 2H, J=8.0), 7.82 (d, 2H, J=8.0), 7.42 (d,2H, J=8.0), 7.33 (d, 2H, J=8.0), 6.20 (br s, 1H), 5.20 (br s, 1H), 4.30(s, 2H), 4.22 (d, 1H, J_(ab)=16), 4.14 (d, 1H, J_(ab)=16), 3.25 (t, 1H,J=6.0), 1.95 (m, 1H), 1-60 (m, 2H), 0.98 (d, 3H, J=7.0), 0.94 (d, 3H,J=7.0)

(2R)-2-{(4-Chlorobenzenesulfonyl)-[4-(2-dimethylamino-acetylamino)-benzyl]-amino}-4-methyl-pentanoicacid amide (Example 308)

To a solution of(2R)-2-[[4-(2-bromo-acetylamino)-benzyl]-(4-chlorobenzenesulfonyl)-amino]-4-methyl-pentanoicacid amide (41 mg, 0.77 mmol) in CH₂Cl₂ (2 mL) was added excess 2.0 Mdimethylamine in THF. The reaction mixture was stirred overnight. Thesolvent was removed in vacuo. Purification by flash chromatography(SiO₂, 10% MeOH/CH₂Cl₂) afforded the title compound (24 mg) in 63%yield. MS (ESI), (M+H)⁺ 495.14, ¹H NMR (CDCl₃, 400 MHz) δ 8.85 (s, 1H),8.02 (d, 2H, J=8.0), 7.75 (d, 2H, J=8.0), 7.38 (d, 2H, J=8.0), 7.29 (d,2H, J=8.0), 6.23 (br s, 1H), 5.39 (br s, 1H), 4.62 (m, 4H), 3.25 (t, 1H,J=6.0), 2.95 (s, 6H), 1.95 (m, 1H), 1.60 (m, 2H), 0.98 (d, 3H, J=7.0),0.94 (d, 3H, J=7.0)

Starting Materials

The following α-amino amides were commercially available or obtained bystandard methods from commercially available amino acids:

5,5,5-Trifluoro-2-aminopentanoic acid amide and6,6,6-trifluoro-2-aminohexanoic acid were prepared according to: Ojima,I.; Kato, K.; Nakahashi, K. J. Org. Chem. 1989, 54, 4511.

The benzyl bromide used in the synthesis of the compounds of Examples100 and 155 was prepared according to: Ishihara, Y.; Fujisawa, Y.;Furuyama, N. PCT Int. Appl. WO 9846590; Senanayake, C. H.; Fang, Q. K.;Wilkinson, S. H. PCT Int. Appl. WO 9833789.

The aldehydes required for the synthesis of the compounds of Examples91, 248, 249, 289, 290, and 300 (see Reaction Scheme 2) were prepared asexemplified for 4-(piperidin-1-yl)benzaldehyde. A suspension of4-fluorobenzaldehye (0.48 mL, 4 mmol), K₂CO₃ (522 mg, 4 mmol),piperidine (340 mg, 4 mmol) in DMSO (5 mL) was heated in a sealed tubeat 150° C. for 18 h. after which time, the reaction was concentrated andpurified by silica gel chromatography (CH₂Cl₂, then 2% MeOH/CH₂Cl₂) toafford 4-(piperidin-1-yl)benzaldehyde, 748 mg, 98% yield.

The aldehydes used in the synthesis of the compounds of Examples 317,318, and 320 were prepared as exemplified for4-(piperidin-1-yl)-3-fluorobenzaldehyde. A suspension of4,3-difluorobenzaldehye (500 mg, 3.5 mmol), K₂CO₃ (483 mg, 3.5 mmol),piperidine (298 mg, 3.5 mmol) in DMSO (5 mL) was heated in a sealed tubeat 130° C. for 18 h. The reaction mixture was allowed to cool to rt,concentrated and purified by silica gel chromatography (CH₂Cl₂, then 2%MeOH/CH₂Cl₂) to afford 4-(piperidin-1-yl)-3-fluorobenzaldehyde, 740 mg,99% yield.

The benzyl chloride used in the preparation of the compounds of Examples433, 474, 480, and 500 was prepared by the following method. To asolution of 2-[(4-chloromethyl)phenyl]propan-2-ol (769 mg, 4.16 mmol)(ref: Creary, X.; Mehrsheikh-Mohammadi, M. E.; McDonald, S. J. Org.Chem. 1987, 52, 3254.) in CH₂Cl₂ (14 mL) at −78° C. was added DAST (0.72mL, 5.4 mmol). After 1.5 h, the solution was quenched with water andwarmed to rt. The mixture was extracted with CH₂Cl₂ (3×). The combinedorganic layers were dried (Na₂SO₄) and concentrated. Flash columnchromatography (SiO₂, 0 to 5% EtOAc/hexanes) provided the chloride as apale yellow liquid (512 mg, 66%). ¹H NMR (CDCl₃, 300 MHz) δ 7.30-7.48(m, 4H), 4.58 (s, 2H), 1.70 (s, 3H), 1.63 (s, 3H).

The preparation of the 2-trimethylsilanyl ethyl ester of 4-bromomethylbenzoic acid, which is used in the synthesis of the compound of Example470 is described by Graffner-Nordberg, M.; Sjoedin, K.; Tunek, A.;Hallberg, A. Chem. Pharm. Bull. 1998, 46, 591.

Conditions for Chromatographic Separation of Enantiomeric Mixtures

Condition 1: Example 345 was separated using the following method.4.6×250 mm, 10 μM, Chiracel OJ column, 1.0 mL/min, 85% Hexane/EtOH 0.1%DEA, over 20 min.

Condition 2: Example 346 was separated using the following method.4.6×250 mm, 10 μM, Chiralpak AD column, 1.0 mL/min, 80% Hexane/EtOH0.15% DEA, over 20 min.

Condition 3: Example 347 was separated using the following method.4.6×250 mm, 10 μM, Chiralpak AD column, 1.0 mL/min, 65% Hexane/IPA 0.1%DEA, over 18 min.

Condition 4: Examples 365 and 366 were separated using the followingmethod. 4.6×250 mm, 10 μM, Chiralpak AD column, 1.0 mL/min, 75%Hexane/EtOH 0.15% DEA, over 25 min.

Condition 5: Examples 408 and 409 were separated using the followingmethod. 4.6×250 mm, 10 μM, Chiracel OD column, 1.0 mL/min, 90%Hexane/EtOH 0.15% DEA, over 36 min. TABLE 4

Ex. No. R¹ R² R³ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

172

173

174

175

176

177

178

179

180

181

182

183

184

185

186

187

188

189

190

191

192

193

194

195

196

197

198

199

200

201

202

203

204

205

206

207

208

209

210

211

212

213

214

215

216

217

218

219

220

221

222

223

224

225

226

227

228

229

230

231

232

233

234

235

236

237

238

239

240

241

242

243

244

245

246

247

248

249

250

251

252

253

254

255

256

257

258

259

260

261

262

263

264

265

266

267

268

269

270

271

272

273

274

275

276

277

278

279

280

281

282

283

284

285

286

287

288

289

290

291

292

293

294

295

296

297

298

299

300

301

302

303

304

305

306

307

308

309

310

311

312

313

314

315

316

317

318

319

320

321

322

323

324

325

326

327

328

329

330

331

332

333

334

335

336

337

338

339

340

341

342

343

344

345

346

347

348

349

350

351

352

353

354

355

356

357

358

359

360

361

362

363

364

365

366

367

368

369

370

371

372

373

374

375

376

377

378

379

380

381

382

383

384

385

386

387

388

389

390

391

392

393

394

395

396

397

398

399

400

401

402

403

404

405

406

407

408

409

410

411

412

413

414

415

416

417

418

419

420

421

422

423

424

425

426

427

428

429

430

431

432

433

434

435

436

437

438

439

440

441

442

443

444

445

446

447

448

449

450

451

452

453

454

455

456

457

458

459

460

461

462

463

464

465

466

467

468

469

470

471

472

473

474

475

476

477

478

479

480

481

482

483

484

485

486

487

488

489

490

491

492

493

494

495

496

497

498

499

500

501

Ex. Reaction Calc. Ret. Time/ No. Scheme Appearance MW Method M + H⁺ NMRData 1 1.2 white 424.95 1.76 425.1 ¹H NMR (CDCl₃) δ 7.63 solid Method B(d, 2 H, J = 7.0 Hz), 7.42 (d, 2 H, J = 7.0 Hz), 7.25 (d, 2 H, J = 8.0Hz), 6.79 (d, 2 H, J = 8.0 Hz), 6.25 (s, br, 1 H), 5.35 (s, br, 1 H),4.36 (dd, 2 H, J = 50 Hz, 15 Hz), 4.26 (t, 1 H, J = 7.2 Hz), 3.78 (s, 3H), 1.83 (m, 1 H), 1.18-1.34 (m, 3 H), 0.75 (d, 3 H, J = 7.0 Hz), 0.67(d, 3 H, J = 7.0 Hz). 2 1 white 394.92 1.71 395.2 ¹H NMR (d₆DMSO) δ 7.81solid Method B (d, 2 H, J = 7.0 Hz), 7.60 (d, 2 H, J = 7.0 Hz), 7.50 (s,br, 1 H), 7.41, (d, 2 H, J = 8.0 Hz), 7.32 (m, 2 H), 7.24 (m, 1 H), 7.18(s, br, 1 H), 4.76 (dd, 2 H, J = 50 Hz, 15 Hz), 4.36 (t, 1 H, J = 7.0Hz), 3.33 (s, 3 H), 1.20-1.34 (m, 3 H), 0.79 (d, 3 H, J = 6.0 Hz), 0.46(d, 3 H, J = 6.0 Hz). 3 1 white 462.92 1.71 463.1 ¹H NMR (d₆DMSO) δ 7.83solid Method A (d, 2 H, J = 7.0 Hz), 7.67 (d, 2 H, J = 7.0 Hz),7.57-7.62 (m, 4 H), 7.06 (s, br, 1 H), 4.79 (dd, 2 H, J = 70 Hz, 17 Hz),4.38 (t, 1 H, J = 6.0 Hz), 3.32 (s, 3 H), 1.23-1.35 (m, 3 H), 0.81 (d, 3H, J = 6.0 Hz), 0.50 (d, 3 H, J = 6.0 Hz) 4 1 white 429.37 1.69 429.1 ¹HNMR (d₆DMSO) δ 7.83 solid Method A (d, 2 H, J = 7.0 Hz), 7.61 (d, 2 H, J= 7.0 Hz), 7.52 (s, br, 1 H), 7.41 (d, 2 H, J = 8.2 Hz), 7.37 (d, 2 H, J= 8.2 Hz), 7.03 (s, br, 1 H), 4.70 (dd, 2 H, J = 50 Hz, 15 Hz), 4.35 (t,1 H, J = 7.0 Hz), 1.28-1.30 (m, 3 H), 0.80 (d, 3 H, J = 6.0 Hz), 0.51(d, 3 H, J = 6.0 Hz). 5 1 white 422.98 1.71 423.2 ¹H NMR (d₆DMSO) δ 7.76solid Method A (d, 2 H, J = 7.0 Hz), 7.61 (d, 2 H, J = 7.0 Hz), 7.42 (s,br, 1 H), 7.16-7.20 (m, 5 H), 6.99 (s, br, 1 H), 4.24 (m, 1 H),3.45-3.51 (m, 1 H), 3.10- 3.18 (m, 1 H), 2.52-2.59 (m, 2 H), 1.95- 2.05(m, 1 H), 1.69-1.80 (m, 1 H), 1.55-1.34 (m, 3 H), 0.84 (m, 6 H). 6 1white 419.93 1.45 420.13 ¹H NMR (d₆DMSO) δ 7.84 solid Method A (d, 2 H,J = 8.0 Hz), 7.79 (d, 2 H, J = 8.0 Hz), 7.63 (d, 2 H, J = 8.0 Hz), 7.58(m, 3 H), 7.03 (s, br, 1 H), 4.87 (dd, 2 H, J = 50 Hz, 15 Hz), 4.32 (t,1 H, J = 7.0 Hz), 1.28-11.30 (m, 3 H), 0.81 (d, 3 H, J = 6.0 Hz), 0.53(d, 3 H, J = 6.0 Hz) 7 1 white 412.91 1.58 413.4 ¹H NMR (d₆DMSO) δ 7.81solid Method A (d, 2 H, J = 7.0 Hz), 7.61 (d, 2 H, J = 7.0 Hz), 7.51 (s,br, 1 H) 7.43 (m, 1 H), 7.11-7.14 (m, 2 H), 7.03 (s, br, 1 H), 4.77 (dd,2 H, J = 50 Hz, 15 Hz), 4.33 (t, 1 H, J = 6.0 Hz), 1.21-1.31 (m, 3 H),0.80 (d, 3 H, J = 6.0 Hz), 0.50 (d, 3 H, J = 6.0 Hz) 8 1 white 412.911.58 413.2 ¹H NMR (d₆DMSO) δ 7.82 solid Method A (d, 2 H, J = 8.0 Hz),7.61 (d, 2 H, J = 8.0 Hz), 7.55 (s, br, 1 H) 7.39 (m, 1 H), 7.05-7.32(m, 4 H), 7.03 (s, br, 1 H), 4.78 (dd, 2 H, J = 50 Hz, 15 Hz), 4.38 (t,1 H, J = 6.0 Hz), 1.26-1.32 (m, 3 H), 0.81 (d, 3 H, J = 6.0 Hz), 0.54(d, 3 H, J = 6.0 Hz) 9 1 white 451.03 2.99 451.2 ¹H NMR (d₆DMSO) δ 7.75solid Method C (d, 2 H, J = 8.5 Hz), 7.55 (d, 2 H, J = 8.5 Hz), 7.51 (s,br, 1 H) 7.25-7.29 (m, 4 H), 7.03 (s, br, 1 H), 4.69 (dd, 2 H, J = 25Hz, 14 Hz), 4.35 (m, 1 H), 1.21-1.31 (m, 3 H), 1.25 (s, 9 H) 0.81 (d, 3H, J = 6.0 Hz), 0.46 (d, 3 H, J = 6.0 Hz) 10 1 white 424.95 1.56 425.2¹H NMR (d₆DMSO) δ 7.80 solid Method A (d, 2 H, J = 8.0 Hz), 7.58 (d, 2H, J = 8.0 Hz), 7.50 (s, br, 1 H) 7.21 (m, 1 H), 7.04 (m, 1 H),6.80-6.95 (m, 3 H), 4.70 (dd, 2 H, J = 50 Hz, 15 Hz), 4.37 (m, 1 H),3.70 (s, 3 H), 1.30-1.39 (m, 3 H), 0.81 (d, 3 H, J = 6.0 Hz), 0.52 (d, 3H, J = 6.0 Hz) 11 1 white 463.81 1.76 463 ¹H NMR (d₆DMSO) δ 7.80 solidMethod A (d, 2 H, J = 8.0 Hz), 7.61 (d, 2 H, J = 8.0 Hz), 7.55-7.60 (m,2 H) 7.40 (m, 1 H), 7.10 (s, br, 1 H), 4.72 (dd, 2 H, J = 50 Hz, 15 Hz),4.40 (m, 1 H), 1.26-1.40 (m, 3 H), 0.83 (d, 3 H, J = 6.0 Hz), 0.60 (d, 3H, J = 6.0 Hz) 12 1 white 462.92 1.68 463.1 ¹H NMR (d₆DMSO) δ 7.80 solidMethod A (d, 2 H, J = 8.0 Hz), 7.68-7.80 (m, 2 H), 7.54-7.61 (m, 4 H),7.08 (s, br, 1 H), 4.80 (dd, 2 H, J = 50 Hz, 15 Hz), 4.38 (t, 1 H, J =6.0 Hz), 1.26-1.33 (m, 3 H), 0.82 (d, 3 H, J = 6.0 Hz), 0.52 (d, 3 H, J= 6.0 Hz) 13 1 white 442.94 1.55 443.2 ¹H NMR (d₆DMSO) δ 7.78 solidMethod A (d, 2 H, J = 8.0 Hz), 7.61 (d, 2 H, J = 8.0 Hz), 7.56 (s, br, 1H), 7.05-7.24 (m, 4 H), 4.65 (dd, 2 H, J = 50 Hz, 15 Hz), 4.40 (t, 1 H,J = 6.0 Hz), 3.81 (s, 3 H) 1.28-1.35 (m, 3 H), 0.81 (d, 3 H, J = 6.0Hz), 0.56 (d, 3 H, J = 6.0 Hz) 14 1 white 410.92 1.51 411.2 ¹H NMR(CDCl₃) δ 7.69 solid Method B (d, 2 H, J = 8.0 Hz), 7.45 (d, 2 H, J =8.5 Hz), 7.26 (d, 2 H, J = 8.5 Hz), 6.73 (d, 2 H, J = 8.0 Hz), 6.33 (s,br, 1 H), 5.24 (s, br, 1 H), 4.28 (dd, 2 H, J = 70 Hz, 20 Hz), 4.23 (m,1 H), 1.67- 1.93 (m, 2 H), 1.12-1.32 (m, 2 H), 0.77 (d, 3 H, J = 7.0Hz), 0.68 (d, 3 H, J = 7.0 Hz) 15 1 sticky 408.5 1.58 409.3 ¹H NMR(CDCl₃) δ 7.77 pale Method B (d, 2 H, J = 8.0 Hz), 7.74-7.59 (m, 3 H),yellow 7.02-7.13 (m, 2 H), 6.84 foam (t, 1 H, J = 8.4 Hz), 6.32 (s, br,1 H), 5.31 (s, br, 1 H), 4.48 (dd, 2 H, J = 50 Hz, 17 Hz), 4.26 (m, 1H), 3.85 (s, 3 H), 1.79-1.84 (m, 1 H), 1.25-1.30 (m, 1 H), 1.04-1.11 (m,1 H), 0.72 (d, 3 H, J = 7.0 Hz), 0.63 (d, 3 H, J = 7.0 Hz) 16 1 white426.49 1.63 427.3 ¹H NMR (CDCl₃) δ 7.73-7.77 film Method B (m, 2 H),6.81-7.18 (m, 5 H), 6.29 (s, br, 1 H), 5.37 (s, br, 1 H), 4.45 (dd, 2 H,J = 50 Hz, 17 Hz), 4.26 (m, 1 H), 3.89 (s, 3 H), 1.76-1.84 (m, 1 H),1.26-1.33 (m, 1 H), 1.08-1.17 (m, 1 H), 0.74 (d, 3 H, J = 7.0 Hz), 0.66(d, 3 H, J = 7.0 Hz) 17 1 pale 476.49 1.79 477.2 ¹H NMR (CDCl₃) δ 7.84yellow Method B (d, 2 H, J = 8.0 Hz), 7.72 (d, 1 H, J = 8.0 Hz), solid7.10 (d, 1 H, J = 9.5 Hz), 6.99 (d, 2 H, J = 8.5 Hz), 6.82 (t, 1 H, J =8.5 Hz), 6.21 (s, br, 1 H), 5.35 (s, br, 1 H), 4.46 (dd, 2 H, J = 50 Hz,15 Hz), 4.31 (t, 1 H, J = 7.5 Hz), 3.87 (s, 3 H), 1.78-1.85 (m, 1 H),1.30-1.35 (m, 1 H), 1.12-1.21 (m, 1 H), 0.77 (d, 3 H, J = 7.0 Hz), 0.68(d, 3 H, J = 7.0 Hz) 18 1 pale 476.49 1.76 477.2 ¹H NMR (CDCl₃) δ7.79-7.89 yellow Method B (m, 3 H), 7.59-7.64 (m, 1 H), 7.01-7.08 solid(m, 1 H), 6.83 (t, 1 H, J = 8.8 Hz), 6.25 (s, br, 1 H), 5.42 (s, br, 1H), 4.45 (dd, 2 H, J = 50 Hz, 17 Hz), 4.33 (m, 1 H), 3.88 (s, 3 H),1.78-1.85 (m, 1 H), 1.31- 1.35 (m, 1 H), 1.17-1.23 (m, 1 H), 0.77 (d, 3H, J = 7.0 Hz), 0.70 (d, 3 H, J = 7.0 Hz) 19 1 white 442.94 1.73 443.2¹H NMR (CDCl₃) δ 7.42-7.63 solid Method B (m, 4 H), 7.02-7.10 (m, 2 H),6.86 (t, 1 H, J = 8.5 Hz), 6.24 (s, br, 1 H), 5.42 (s, br, 1 H), 4.45(dd, 2 H, J = 50 Hz, 17 Hz), 4.27 (m, 1 H), 3.87 (s, 3 H), 1.79-1.87 (m,1 H), 1.27-1.33 (m, 1 H), 1.14-1.22 (m, 1 H), 0.78 (d, 3 H, J = 7.0 Hz),0.71 (d, 3 H, J = 7.0 Hz) 20 1 pale 422.52 1.68 423.2 ¹H NMR (CDCl₃) δ7.52-7.57 yellow Method B (m, 2 H), 7.37-7.39 (m, 2 H), 7.02-7.12 oil(m, 2 H), 6.84 (t, 1 H, J = 8.5 Hz), 6.34 (s, br, 1 H), 5.35 (s, br, 1H), 4.45 (dd, 2 H, J = 50 Hz, 17 Hz), 4.25 (m, 1 H), 3.86 (s, 3 H), 2.38(s, 3 H), 1.78-1.87 (m, 1 H), 1.25-1.31 (m, 1 H), 1.04-1.11 (m, 1 H),0.72 (d, 3 H, J = 7.0 Hz), 0.65 (d, 3 H, J = 7.0 Hz) 21 1 pale 422.521.67 423.2 ¹H NMR (CDCl₃) δ 7.64 yellow Method B (d, 2 H, J = 8.0 Hz),7.25-7.30 (m, 2 H), oil 7.02-7.12 (m, 2 H), 6.84 (t, 1 H, J = 8.5 Hz),6.34 (s, br, 1 H), 5.32 (s, br, 1 H), 4.45 (dd, 2 H, J = 50 Hz, 17 Hz),4.26 (t, 1 H, J = 10 Hz), 3.86 (s, 3 H), 2.42 (s, 3 H), 1.76-1.85 (m, 1H), 1.25-1.31 (m, 1 H), 1.05-1.12 (m, 1 H), 0.72 (d, 3 H, J = 7.0 Hz),0.62 (d, 3 H, J = 7.0 Hz) 22 3 clear 455.02 1.94 455.2 ¹H NMR (d₆DMSO) δ7.82 oil Method B (d, 2 H, J = 8.0 Hz), 7.68 (d, 2 H, J = 8.0 Hz), 7.56(s, br, 1 H), 7.45 (m, 1 H), 7.16 (m, 1 H), 7.04 (s, 1 H), 6.86 (m, 1H), 4.25 (m, 1 H), 3.94 (m, 1 H), 3.40-3.55 (m, 2 H), 3.02-3.14 (m, 1H), 1.18-1.69 (m, 10 H), 0.76 (s, br, 6 H). 23 1 white 441.01 1.67 441.2¹H NMR (d₆DMSO) δ 7.79 solid Method A (d, 2 H, J = 8.0 Hz), 7.59 7.51(s, br, 1 H), 7.31 (d, 2 H, J = 8.0 Hz), 7.19 (d, 2 H, J = 8.0 Hz), 7.03(s, br, 1 H), 4.68 (dd, 2 H, J = 50 Hz, 15 Hz), 4.35 (t, 1 H, J = 7.0Hz), 3.32 (s, 3 H), 1.24-1.35 (m, 3 H), 0.81 (d, 3 H, J = 6.0 Hz), 0.51(d, 3 H, J = 6.0 Hz) 24 1 white 467.86 1.75 469.1 ¹H NMR (d₆DMSO) δ 7.83solid Method A (d, 2 H, J = 8.0 Hz), 7.64 (d, 2 H, J = 8.0 Hz), 7.42 (s,br, 1 H), 7.01 (s, 1 H), 4.25 (m, 1 H), 3.35-3.51 (m, 3 H), 3.08-3.14(m, 1 H), 1.19-1.82 (m, 11 H), 0.86 (d, 6 H, J = 6.0 Hz). 25 3 clear474.07 1.34 474.4 ¹H NMR (d₆DMSO) δ 7.82 oil Method A (d, 2 H, J = 8.0Hz), 7.64 (d, 2 H, J = 8.0 Hz), 7.42 (s, br, 1 H), 6.99 (s, 1 H), 4.25(m, 1 H), 3.51-3.60 (s, br, 4 H), 3.18-3.41 (m, 2 H), 2.25- 2.35 (s, br,4 H), 2.27 (m, 2 H) 1.15-1.62 (m, 9 H), 0.80 (d, 6 H, J = 6.0 Hz). 26 3clear 472.09 1.27 472 ¹H NMR (d₆DMSO) δ 7.83 oil Method A (d, 2 H, J =8.0 Hz), 7.64 (d, 2 H, J = 8.0 Hz), 7.42 (s, br, 1 H), 7.00 (s, 1 H),4.23-4.26 (m, 1 H), 3.22-3.45 (m, 1 H), 3.11-3.14 (m, 1 H), 2.16-2.28(m, 5 H), 1.19-1.52 (m, 18 H), 0.86 (m, 6 H). 27 3 clear 490.13 1.21 490¹H NMR (d₆DMSO) δ 7.83 oil Method A (d, 2 H, J = 8.0 Hz), 7.64 (d, 2 H,J = 8.0 Hz), 7.44 (s, br, 1 H) 7.06 (s, 1 H), 4.21-4.25 (m, 1 H), 3.55(s, br, 4 H), 3.19-3.40 (m, 4 H), 2.43-2.57 (m, 8 H), 2.23-2.30 (m, 2H), 1.18-1.59 (m, 9 H), 0.82 (m, 6 H). 28 3 clear 446.01 1.08 446.2 ¹HNMR (d₆DMSO) δ 7.84 oil Method A (d, 2 H, J = 8.0 Hz), 7.66 (d, 2 H, J =8.0 Hz), 7.49 (s, br, 1 H), 7.02 (s, 1 H), 4.23-4.26 (m, 1 H), 3.94 (s,br, 2 H), 3.71 (s, br, 2 H), 3.52-3.57 (m, 1 H), 3.14-3.17 (m, 1 H),3.06 (s, br, 4 H), 1.17-1.65 (m, 7 H), 0.86 (m, 6 H). 29 1 white 428.911.51 429.1 ¹H NMR (CDCl₃) δ 7.69 solid Method A (d, 2 H, J = 9.0 Hz),7.47 (d, 2 H, J = 9.0 Hz), 7.13 (d, 1 H, J = 11.2 Hz), 7.00 (d, 1 H, J =8.0 Hz), 6.88 (m, 1 H), 6.27 (s, br, 1 H), 5.49 (s, br, 1 H), 5.24 (s,br, 1 H), 4.40 (dd, 2 H, J = 90 Hz, 18 Hz), 3.20 (m, 1 H), 1.09-1.82 (m,3 H), 0.77 (d, 3 H, J = 7.0 Hz), 0.68 (d, 3 H, J = 7.0 Hz). 30 1 white484.59 1.89 485.0 ¹H NMR (CDCl₃) δ 7.73 solid Method A (d, 2 H, J = 8.0Hz), 7.65 (d, 2 H, J = 8.0 Hz) 7.18-7.27 (m, 4 H), 6.25 (s, br, 1 H),5.29 (s, br, 1 H), 4.40- 4.69 (m, 3 H), 1.80-1.88 (m, 1 H), 1.29 (s, 9H), 1.25-1.33 (m, 2 H), 0.80 (d, 3 H, J = 7.0 Hz), 0.69 (d, 3 H, J = 7.0Hz) 31 1 white 430.61 1.82 431.2 ¹H NMR (CDCl₃) δ 7.60 solid Method A(d, 2 H, J = 8.2 Hz), 7.24-7.39 (m, 6 H), 6.34 (s, br, 1 H), 5.19 (s,br, 1 H), 4.42- 4.44 (m, 2 H), 4.30 (t, 1 H, J = 8 Hz), 2.41 (s, 3 H),1.74-1.83 (m, 1 H), 1.28 (s, 9 H), 1.25-1.33 (m, 1 H), 0.93-1.01 (m, 1H), 0.72 (d, 3 H, J = 7.0 Hz), 0.60 (d, 3 H, J = 7.0 Hz) 32 3 brown460.04 1.15 460.2 ¹H NMR (d₆DMSO) δ 7.83 oil Method A (d, 2 H, J = 8.0Hz), 7.64 (d, 2 H, J = 8.0 Hz), 7.42 (s, br, 1 H) 7.00 (s, 1 H),4.22-4.26 (m, 1 H), 3.55 (s, br, 4 H), 3.11-3.32 (m, 2 H), 2.13-2.37 (m,6 H), 1.12-1.51 (m, 9 H), 0.86 (m, 6 H). 33 1 white 400.97 1.85 401 ¹HNMR (d₆DMSO) δ 7.85 solid Method A (d, 2 H, J = 8.0 Hz), 7.65 (d, 2 H, J= 8.0 Hz), 7.32 (s, br, 1 H) 7.05 (s, br, 1 H), 4.19 (t, 1 H, J = 7.5Hz), 2.99- 3.02 (m, 1 H), 1.07-1.65 (m, 14 H), 0.78-0.84 (m, 7 H). 34 3clear 476.1 1.28 476.1 ¹H NMR (CDCl₃) δ 7.76 Oil Method A (d, 2 H, J =8.0 Hz), 7.51 (d, 2 H, J = 8.0 Hz), 6.55 (s, br, 1 H), 5.41 (s, 1 H),4.17-4.20 (m, 1 H), 3.26- 3.38 (m, 1 H), 3.13-3.17 (m, 1 H), 2.62-2.92(m, 8 H), 2.32-2.36 (m, 2 H), 1.85-1.87 (m, 1 H), 1.25-1.47 (m, 7 H),0.96-0.99 (m, 1 H), 0.75 (d, 3 H, J = 6.6 Hz), 0.72 (d, 2 H, J = 6.6Hz). 35 3 clear 462.08 1.31 462.2 ¹H NMR (CDCl₃) δ 7.75 oil Method A (d,2 H, J = 8.0 Hz), 7.52 (d, 2 H, J = 8.0 Hz), 6.51 (s, br, 1 H), 6.05 (s,1 H), 4.15-4.18 (m, 1 H), 3.56- 3.78 (m, 4 H), 3.45-3.47 (m, 1 H),3.09-3.14 (m, 1 H), 2.90-3.08 (m, 4 H), 2.61-2.69 (m, 2 H), 1.62-2.05(m, 5 H), 1.21-1.29 (m, 1 H), 0.80-0.83 (m, 1 H), 0.78 (d, 3 H, J = 6.6Hz), 0.71 (d, 2 H, J = 6.6 Hz). 36 3 clear 418.0 1.25 418.2 ¹H NMR(CDCl₃) δ 7.77 oil Method A (d, 2 H, J = 8.5 Hz), 7.51 (d, 2 H, J = 8.5Hz), 6.56 (s, br, 1 H), 5.41 (s, 1 H), 4.18-4.21 (m, 1 H), 3.15-3.32 (m,2 H), 2.25-2.28 (m, 2 H), 2.24 (s, 6 H), 1.84-1.88 (m, 1 H), 1.25-1.49(m, 7 H), 0.97-1.00 (m, 1 H), 0.71- 0.74 (m, 6 H). 37 1 tan 428.91 1.5429.1 ¹H NMR (CDCl₃) δ 7.57 solid Method A (d, 2 H, J = 8.0 Hz), 7.38(d, 2 H, J = 9.0 Hz), 7.03-7.13 (m, 2 H), 6.80 (t, 1 H, J = 8.8 Hz),6.17 (s, br, 1 H), 5.39 (s, br, 1 H), 4.48 (dd, 2 H, J = 55 Hz, 16 Hz),3.84 (s, 3 H), 3.75- 3.84 (m, 1 H), 1.11-1.30 (m, 1 H), 0.91 (d, 3 H, J= 7.0 Hz), 0.54 (d, 3 H, J = 7.0 Hz). 38 1 white 412.46 1.46 413.2 ¹HNMR (CDCl₃) δ 7.65-7.70 solid Method A (m, 2 H), 7.04-7.12 (m, 4 H),6.79 (t, 1 H, J = 8.5 Hz), 6.21 (s, br, 1 H), 5.27 (s, br, 1 H), 4.48(dd, 2 H, J = 50 Hz, 15 Hz), 3.86 (s, 3 H), 3.79- 3.85 (m, 1 H),2.16-2.22 (m, 1 H), 0.90 (d, 3 H, J = 7.0 Hz), 0.51 (d, 3 H, J = 7.0Hz). 39 1 white 403.48 1.47 404.2 ¹H NMR (CDCl₃) δ 7.77-7.80 solidMethod A (m, 2 H), 7.59 (d, 2 H, J = 8.0 Hz), 7.49 (d, 2 H, J = 8.0 Hz),7.17-7.22 (m, 2 H), 6.17 (s, br, 1 H), 5.20 (s, br, 1 H), 4.50 (dd, 2 H,J = 60 Hz, 17 Hz), 4.28 (t, 1 H, J = 10 Hz), 1.74-1.83 (m, 1 H),1.25-1.33 (m, 1 H), 0.99-1.10 (m, 1 H), 0.77 (d, 3 H, J = 7.0 Hz), 0.66(d, 3 H, J = 7.0 Hz). 40 1 white 453..49 1.65 454.1 ¹H NMR (CDCl₃) δ7.88 solid Method A (d, 2 H, J = 8.2 Hz), 7.78 (d, 2 H, J = 8.5 Hz),7.59 (d, 2 H, J = 8.5 Hz), 7.49 (d, 2 H, J = 8.5 Hz), 6.10 (s, br, 1 H),5.19 (s, br, 1 H), 4.59 (dd, 2 H, J = 50 Hz, 16 Hz), 4.33 (t, 1 H, J =10 Hz), 1.76-1.81 (m, 1 H), 1.25-1.35 (m, 1 H), 1.02-1.07 (m, 1 H), 0.78(d, 3 H, J = 7.0 Hz), 0.65 (d, 3 H, J = 7.0 Hz) 41 1 white 399.52 1.53400.2 ¹H NMR (CDCl₃) δ 7.65 solid Method A (d, 2 H, J = 8.0 Hz), 7.58(d, 2 H, J = 8.2 Hz), 7.47 (d, 2 H, J = 8.0 Hz), 7.31 (d, 2 H, J = 8.5Hz), 6.24 (s, br, 1 H), 5.16 (s, br, 1 H), 4.50 (dd, 2 H, J = 50 Hz, 17Hz), 4.27 (t, 1 H, J = 10 Hz), 2.44 (s, 3 H), 1.74- 1.83 (m, 1 H),1.25-1.33 (m, 1 H), 0.93-1.01 (m, 1 H), 0.74 (d, 3 H, J = 7.0 Hz), 0.63(d, 3 H, J = 7.0 Hz) 42 3 clear 441.0 1.27 441.2 ¹H NMR (CDCl₃) δ 7.74oil Method A (d, 2 H, J = 8.2 Hz), 7.67 (s, 1 H), 7.50 (d, 2 H, J = 8.2Hz), 7.10 (s, 1 H)). 6.93 (s, 1 H), 6.51 (s, br, 1 H), 5.55 (s, br, 1H), 4.14-4.17 (m, 1 H), 3.97 (t, 2 H, J = 6.0 Hz), 3.29-3.35 (m, 1 H),3.09-3.14 (m, 1 H), 1.62-1.66 (m, 3 H), 1.55-1.62 (m, 2 H), 1.25- 1.29(m, 3 H), 0.80-0.83 (m, 1 H), 0.74 (d, 3 H, J = 6.6 Hz), 0.71 (d, 2 H, J= 6.6 Hz). 43 3 clear 446.06 1.29 446.3 ¹H NMR (CDCl₃) δ 7.76 oil MethodA (d, 2 H, J = 8.0 Hz), 7.52 (d, 2 H, J = 8.0 Hz), 6.61 (s, br, 1 H)5.45 (s, 1 H), 4.15-4.18 (m, 1 H), 3.09-3.24 (m, 2 H), 2.50-2.58 (m, 4H), 2.31-2.39 (m, 2 H), 1.92-1.99 (m, 1 H), 1.15- 1.59 (m, 8 H),1.00-1.04 (m, 7 H), 0.71-0.74 (m, 6 H). 44 1 tan 428.91 1.58 429.1 ¹HNMR (CDCl₃) δ 7.67 wax Method A (d, 2 H, J = 8.0 Hz), 7.45 (d, 2 H, J =9.0 Hz), 7.03-7.15 (m, 2 H), 6.84 (t, 1 H, J = 8.0 Hz), 6.25 (s, br, 1H), 5.19 (s, br, 1 H), 4.45 (dd, 2 H, J = 80 Hz, 18 Hz), 4.19-4.22 (m, 1H), 3.87 (s, 3 H), 1.82-1.95 (m, 1 H), 0.96- 1.30 (m, 3 H), 0.72-0.77(m, 3 H). 45 3 clear 506.11 1.39 506.2 ¹H NMR (CDCl₃) δ 7.75 oil MethodA (d, 2 H, J = 8.0 Hz), 7.50 (d, 2 H, J = 8.5 Hz), 7.01-7.13 (m, 4 H),6.55 (s, br, 1 H), 5.39 (s, br, 1 H), 4.18 (t, 1 H, J = 6.0 Hz),3.32-3.60 (m, 1 H), 3.16-19 (m, 1 H), 2.91 (s, br, 2 H), 2.76 (s, br, 2H), 2.52 (s, br, 2 H), 1.27-1.86 (m, 8 H), 0.97- 1.00 (m, 1 H), 0.73 (m,6 H). 46 1 white 418.94 2.7 441 ¹H NMR (d₆DMSO) δ 7.89 solid Method A(M + Na⁺) (d, 2 H, J = 8.2 Hz), 7.65 (d, 2 H, J = 8.4 Hz), 7.52 (s, br,1 H), 7.00 (s, br, 1 H), 4.25 (dd, 2 H, J = 80 Hz, 18 Hz), 4.10-4.13 (m,1 H), 2.59-2.60 (m, 1 H), 1.35 (s, 9 H), 1.32-1.35 (m, 2 H), 0.860 (d, 3H, J = 6.0 Hz), 0.75 (d, 3 H, J = 6.0 Hz). 47 1 yellow 439.92 1.69 440.2¹H NMR (CDCl₃) δ 8.17 solid Method A (d, 2 H, J = 7.0 Hz), 7.72 (d, 2 H,J = 7.0 Hz), 7.54 (d, 1 H, J = 8.8 Hz), 7.49 (d, 1 H, J = 8.8 Hz), 6.14(s, br, 1 H), 5.18 (s, br, 1 H), 4.60 (dd, 2 H, J = 70 Hz, 18 Hz),4.29-4.34 (m, 1 H), 1.74-1.83 (m, 1 H), 1.00-1.34 (m, 2 H), 0.78 (d, 3H, J = 7.0 Hz), 0.67 (d, 3 H, J = 7.0 Hz). 48 4 tan 409.94 1.26 410.1 ¹HNMR (CDCl₃) δ 7.80 solid Method A (d, 2 H, J = 8.5 Hz), 7.63 (d, 2 H, J= 8.5 Hz), 7.52 (s, br, 1 H), 7.46 (d, 1 H, J = 8.0 Hz), 7.26 (d, 1 H, J= 8.0 Hz), 7.02 (s, br, 1 H), 4.70 (dd, 2 H, J = 50 Hz, 18 Hz), 4.30-4.41 (m, 1 H), 3.67 (s, br, 2 H), 1.28- 1.33 (m, 3 H), 0.86 (d, 3 H, J =7.0 Hz), 0.57 (d, 3 H, J = 7.0 Hz). 49 3 Tan 431.99 1.19 432 ¹H NMR(d₆DMSO) δ 7.81 foam Method A (d, 2 H, J = 8.0 Hz), 7.66 (d, 2 H, J =8.0 Hz), 7.45 (s, br, 1 H) 7.02 (s, 1 H), 4.27 (m, 1 H), 3.56 (s, br, 4H), 3.55-3.57 (m, 1 H), 3.08-3.14 (m, 1 H), 2.22-2.32 (m, 6 H),1.79-1.82 (m, 11 H), 1.17-1.62 (m, 4 H), 0.86 (d, 6 H, J = 6.0 Hz). 50 1white 436.51 1.58 437.1 ¹H NMR (CDCl₃) δ 7.95 solid Method A (d, 2 H, J= 8.0 Hz), 7.74-7.79 (m, 2 H), 7.42 (d, 2 H, J = 8.0 Hz), 7.14- 7.19 (m,2 H) 6.24 (s, br, 1 H), 5.20 (s, br, 1 H), 4.50 (dd, 2 H, J = 50 Hz, 17Hz), 4.12 (m, 1 H), 3.91 (s, 3 H), 1.75-1.82 (m, 1 H), 1.25-1.31 (m, 1H), 1.05-1.12 (m, 1 H), 0.75 (d, 3 H, J = 7.0 Hz), 0.64 (d, 3 H, J = 7.0Hz) 51 4 tan 423.97 1.21 424.1 ¹H NMR (CDCl₃) δ 7.65 solid Method A (d,2 H, J = 8.0 Hz), 7.58 (d, 2 H, J = 8.2 Hz), 7.47 (d, 2 H, J = 8.0 Hz),7.31 (d, 2 H, J = 8.5 Hz), 6.24 (s, br, 1 H), 5.16 (s, br, 1 H), 4.50(dd, 2 H, J = 50 Hz, 17 Hz), 4.27 (t, 1 H, J = 10 Hz), 2.44 (s, 3 H),1.74-1.83 (m, 1 H), 1.25- 1.33 (m, 1 H), 0.93-1.01 (m, 1 H), 0.74 (d, 3H, J = 7.0 Hz), 0.63 (d, 3 H, J = 7.0 Hz) 52 1 white 448.90 1.79 449.0¹H NMR (CDCl₃) δ 7.66 solid Method A (d, 2 H, J = 8.5 Hz), 7.43 (d, 2 H,J = 8.5 Hz), 7.12 (d, 1 H, J = 8.0 Hz), 6.49 (d, 1 H, J = 8.0 Hz), 6.24(s, br, 1 H), 5.22 (s, br, 1 H), 4.35 (dd, 2 H, J = 50 Hz, 15 Hz),4.22--4.27 (m, 1 H), 2.04 (s, 3 H), 1.27-1.89 (m, 3 H), 0.74 (d, 3 H, J= 7.0 Hz), 0.68 (d, 3 H, J = 7.0 Hz). 53 1-Method A white 424.95 1.58425.2 ¹H NMR (DMSO-d₆, 500 MHz) δ solid Method A 7.82 (d, 2 H, J = 8.2),7.62 (d, 2 H, J = 8.3), 7.44 (d, 2 H, J = 7.1), 7.21 (t, 1 H, J = 6.7),6.97 (s, 1 H), 6.92 (d, 2 H, J = 6.9), 4.99 (d, 1 H), J = 17), 4.40 (d,1 H, J = 17), 4.33 (br s, 1 H), 3.76 (s, 3 H), 1.20-1.40 (m, 3 H), 0.79(d, 3 H, 5.2), 0.54 (d, 3 H, J = 5.2). 54 1-Method A white 400.86 1.81398.94 ¹H NMR (CDCl₃) δ 7.71 (d, 2 H, solid min (M − H⁻) J = 6.8 Hz),7.48 (d, 2 H, J = 6.8 Hz), Method B 7.15 (d, 2 H, J = 10 Hz), 7.02 (d, 2H, J = 8.0 Hz), 6.85 (t, 1 H, J = 7.5 Hz), 6.19 (s, br, 1 H), 5.13 (s,br, 1 H), 4.31 (dd, 2 H, J = 50 Hz, 15 Hz), 4.43-4.45 (m, 1 H), 3.87 (s,3 H), 1.17 (d, 3 H, J = 6.8 Hz). 55 1-Method A white 478.92 1.76 479.1¹H NMR (DMSO-d₆, 500 MHz) δ solid Method A 7.81 (d, 2 H, J = 8.5), 7.60(d, 2 H, J = 8.2), 7.54 (s, 1 H), 7.51 (d, 2 H, J = 8.5), 7.30 (d, 2 H,J = 8.2), 7.04 (s, 1 H), 4.83 (d, 1 H), J = 17), 4.71 (d, 1 H, J = 17),1.20-1.35 (m, 3 H), 0.80 (d, 3 H, J = 6.1), 0.47 (d, 3 H, J = 6.2). 561-Method A white 434.58 1.95 435.24 ¹H NMR (CDCl₃, 300 MHz) δ 7.67 solidmin (dd, 2 H, J = 5.0, 8.9), 7.20-7.30 (m, Method A 4 H), 7.09 (dd, 2 H,J = 8.6, 8.6), 6.28 (br s, 1 H), 5.24 (br s, 1 H), 4.44 (s, 2 H), 4.34(t, 1 H, J = 7.8), 1.75-1.90 (m, 1 H), 1.22-1.38 (m, 2 H), 1.30 (s, 9H), 0.77 (d, 3 H, J = 6.4), 0.67 (d, 3 H, J = 6.4). 57 3 brown 458.072.16 458.2 ¹H NMR (CDCl₃, 500 MHz) δ 7.77 oil Method C (dd, 2 H, J =1.6, 6.8), 7.53 (dd, 2 H, J = 2.0, 6.7), 6.55 (s, 1 H), 5.64 (s, 1 H),4.15 (dd, 1 H, J = 5.6, 9.2), 3.57 (t, 2 H, J = 12), 3.35-3.45 (m, 1 H),3.10- 3.17 (m, 1 H), 2.87-3.00 (m, 2 H), 2.57-2.70 (m, 2 H), 2.27-2.40(m, 2 H), 1.80-2.00 (m, 6 H), 1.63-1.73 (m, 2 H), 1.20-1.50 (m, 4 H),0.85- 0.90 (m, 1 H), 0.73 (d, 3 H, J = 6.4), 0.70 (d, 3 H), J = 6.9 58 5colorless 390.89 1.51 391.2 ¹H NMR (CDCl₃, 500 MHz) δ 7.91 oil Method A(dd, 2 H, J = 2.0, 6.8), 7.51 (dd, 2 H, J = 2.2, 6.9), 7.06 (s, 1 H),5.33 (s, 1 H), 4.13-4.25 (m, 2 H), 4.03-4.15 (m, 3 H), 1.77-1.85 (m, 1H), 1.35-1.45 (m, 1 H), 1.30 (t, 3 H, J = 7.1), 1.15- 1.22 (m, 1 H),0.74 (d, 3 H, J = 6.6), 0.71 (d, 3 H, J = 6.5). 59 5 white 362.83 1.28363.1 ¹H NMR (DMSO-d₆, 500 MHz) δ 7.90 solid Method A (dd, 2 H, J = 2.0,6.8), 7.65 (dd, 2 H, J = 2.0, 6.8), 7.60 (s, 1 H), 7.06 (s, 1 H), 4.32(d, 1 H, J = 18), 4.12 (t, 1 H, J = 8.0), 4.02 (d, 1 H, J = 18),1.55-1.65 (m, 1 H), 1.35-1.45 (m, 2 H), 0.78 (d, 3 H, J = 6.1), 0.73 (d,3 H, J = 6.1). 60 1-solid white 408.95 1.82 409.1 ¹H NMR (CDCl₃) δ 7.64(d, 2 H, support solid min J = 8.0 Hz), 7.44 (d, 2 H, J = 8.0 Hz),Method B 7.22 (d, 2 H, J = 8.0 Hz), 7.08 (d, 2 H, J = 8.0 Hz), 6.29 (s,br, 1 H), 5.34 (s, br, 1 H), 4.53 (d, 1 H, J = 15.20 Hz), 4.34 (d, 1 H),J = 15.20 Hz), 4.27 (t, 1 H, J = 7.2 Hz), 2.32 (s, 3 H), 1.84 (m, 1 H),1.30 (m, 1 H), 1.21 (m, 1 H), 0.75 (d, 3 H, J = 6.8 Hz), 0.67 (d, 3 H, J= 6.8 Hz) 61 1-Method A white 452.96 1.85 453.08 ¹H NMR (CDCl₃, 300 MHz)δ 7.97 solid min (dd, 2 H, J = 1.7, 8.4), 7.68 (dd, 2 H, J = Method A2.0, 8.7), 7.41-7.48 (m, 4 H), 6.23 (br s, 1 H), 5.16 (br s, 1 H), 4.64(d, 1 H, J = 15.8), 4.47 (d, 1 H, J = 15.9), 4.31 (t, 1 H, J = 7.8),3.92 (s, 3 H), 1.76-1.83 (m, 1 H), 1.26-1.35 (m, 1 H), 1.08-1.13 (m, 1H), 0.76 (d, 3 H, J = 6.0), 0.65 (d, 3 H, J = 6.7). 62 1-solid white430.95 1.81 431.06 ¹H NMR (CDCl₃) δ 7.72 (d, 2 H, support solid min J =8.0 Hz), 7.49 (d, 2 H, J = 8.0 Hz), Method B 7.24 (m, 1 H), 6.95 (m, 2H), 6.25 (s, br, 1 H), 5.27 (s, br, 1 H), 4.62 (d, 1 H, J = 16.0 Hz),4.45 (d, 1 H, J = 16 Hz), 4.33 (t, 1 H, J = 6.8 Hz), 1.84 (m, 1 H), 1.30(m, 1 H), 1.21 (m, 1 H), 0.78 (d, 3 H, J = 6.8 Hz), 0.70 (d, 3 H, J =6.8 Hz) 63 1-solid pale 471.02 2.04 471.09 ¹H NMR (CDCl₃) δ 7.65 (d, 2H, support yellow min J = 8.0 Hz), 7.58 (d, 2 H, J = 8.0 Hz), solidMethod B 7.47 (d, 2 H, J = 8.0 Hz), 7.37-7.44 (m, 6 H), 6.27 (s, br, 1H), 5.33 (s, br, 1 H), 4.58 (d, 1 H, J = 15.2 Hz), 4.45 (d, 1 H, J =15.2 Hz), 4.36 (t, 1 H, J = 7.2 Hz), 1.84 (m, 1 H), 1.30 (m, 1 H), 1.21(m, 1 H), 0.78 (d, 3 H, J = 6.8 Hz), 0.70 (d, 3 H, J = 6.8 Hz) 641-solid pale 372.92 1.82 395.11 ¹H NMR (CDCl₃) δ 7.65 (d, 2 H supportpink min M + Na J = 8.0 Hz), 7.50 (d, 2 H, J = 8.0 Hz), solid Method B6.75 (s, br, 1 H), 6.70 (s, br, 1 H), 5.04 (m, 1 H), 4.32 (t, 1 H, J =7.2 Hz), 3.91 (d br, 2 H, J = 7.0 Hz), 1.81 (m, 1 H), 1.66 (s br, 6 H),1.30 (m, 1 H), 1.21 (m, 1 H), 0.77 (d, 3 H, J = 6.5 Hz), 0.76 (d, 3 H, J= 6.5 Hz) 65 4 white 437.99 1.39 438.1 ¹H NMR (DMSO-d₆, 500 MHz) δ solidMethod A 7.74 (dd, 2 H, J = 1.9, 6.7), 7.5 (dd, 2 H, J = 1.9, 6.8), 7.43(s, 1 H), 7.16 (d, 2 H, J = 8.6), 7.01 (s, 1 H), 6.61 (d, 2 H, J = 8.8),4.59 (q, 2 H, J = 16, 25), 4.34 (dd, 1 H, J = 5.0, 9.3), 2.85 (s, 6 H),1.27-1.47 (m, 3 H), 0.80 (d, 3 H, J = 5.9), 0.52 (d, 3 H, J = 6.1). 661-Method A white 473.01 1.58 437.0 ¹H NMR (DMSO-d₆, 500 MHz) δ solidMethod A 7.87 (d, 2 H, J = 8.2), 7.83 (d, 2 H, J = 8.3), 7.64 (d, 2 H, J= 8.5 Hz), 7.63 (d, 2 H, J = 8.5), 7.59 (s, 1 H), 7.08 (s, 1 H), 4.92(d, 1 H, J = 17), 4.76 (d, 1 H, J = 17), 4.39 (t, 1 H, J = 6.9), 3.35(br s, 1 H), 1.20-1.40 (m, 3 H), 0.81 (d, 3 H, J = 6.2), 0.54 (d, 3 H, J= 6.2). 67 1-Method A colorless 346.88 1.79 347.1 ¹H NMR (DMSO-d₆, 500MHz) δ oil Method A 7.83 (d, 2 H, J = 8.8 Hz), 7.63 (d, 2 H, J = 8.6),7.41 (s, 1 H), 7.0 (s, 1 H), 4.25 (dd, 1 H, J = 4.8, 8.9), 3.38-3.47 (m,1 H), 3.0-3.13 (m, 1 H), 1.55-1.70 (m, 1 H), 1.40-1.55 (m, 1 H),1.30-1.40 (m, 1 H), 0.87 (t, 3 H, J = 7.6), 0.73 (d, 3 H, J = 6.4), 0.72(d, 3 H, J = 6.7). 68 3 white 448.05 1.25 448.19 ¹H NMR (CDCl₃, 500 MHz)δ 7.76 oil min (dd, 2 H, J = 2.0, 6.7), 7.50 (dd, 2 H, J = Method C 2.0,6.7), 6.51 (s, 1 H), 5.45 (s, 1 H), 4.20 (dd, 1 H, J = 6.4, 8.2),3.35-3.45 (m, 1 H), 3.20-3.30 (m, 1 H), 2.68 (br s, 8 H), 2.35 (br s, 2H), 1.70-1.90 (m, 3 H), 1.20-1.40 (m, 1 H), 0.95-1.05 (m, 1 H), 0.75 (d,3 H, J = 4.3), 0.73 (d, 3 H, J = 4.4). 69 6 white 422.48 1.56 423.14 ¹HNMR (CDCl₃, 500 MHz) δ 7.89- solid min 7.93 (m, 4 H), 7.84 (br s, 1 H),7.49 Method A (d, 2 H, J = 8.2), 7.24-7.29 (m, 2 H), 6.58 (br s, 1 H),5.12 (d, 1 H, J = 15.3), 4.23 (dd, 1 H, J = 4.6, 9.7), 4.05 (d, 1 H, J =15.4), 2.04-2.14 (m, 1 H), 1.23-1.32 (m, 1 H), 0.79-0.88 (m, 1 H), 0.72(d, 3 H, J = 6.6), 0.67 (d, 3 H, J = 6.6). 70 1-Method A white 466.891.77 467.03 ¹H NMR (CDCl₃) δ 7.65 (d, 2 H, solid min J = 6.8 Hz),7.52-7.56 (m, 2 H), 7.47 (d, Method B 2 H, J = 6.8 Hz), 7.11 (t, 1 H, J= 8.5 Hz), 6.22 (s, br, 1 H), 5.24 (s, br, 1 H), 4.41 (dd, 2 H, J = 50Hz, 15 Hz), 4.28 (t, 1 H, 7.5 Hz), 1.80-1.92 (m, 1 H), 1.21-1.30 (m, 1H), 0.95-1.19 (m, 2 H), 0.76 (t, 3 H, J = 7.0 Hz). 71 1-Method A white398.89 1.80 388.0 ¹H NMR (CDCl₃) δ 7.67 (d, 2 H, wax min J = 8.0 Hz)7.54 (d, 2 H, J = 8.0 Hz), Method B 7.42-7.49 (m, 4 H), 6.20 (s, br, 1H), 5.21 (s, br, 1 H), 4.54 (dd, 2 H, J = 50 Hz, 15 Hz), 4.25-4.29 (m, 1H), 1.82-1.95 (m, 1 H), 1.26-1.33 (m, 1 H), 0.98-1.12 (m, 2 H), 0.75 (t,3 H, J = 7.0 Hz). 72 1-Method A white 482.01 1.79 482.06 ¹H NMR (CDCl₃)δ 7.76 (d, 1 H, solid min J = 7.5 Hz), 7.63-7.67 (m, 4 H), 7.43- MethodB 7.50 (m, 8 H), 6.24 (s, br, 1 H), 5.28 (s, br, 1 H), 4.53 (dd, 2 H, J= 50 Hz, 15 Hz), 4.27 (t, 1 H, J = 7.3 Hz), 1.87- 1.99 (m, 1 H),1.30-1.39 (m, 1 H), 1.03-1.11 (m, 2 H), 0.76 (t, 3 H, J = 8.0 Hz). 731-Method A pale 426.90 1.86 427.09 ¹H NMR (CDCl₃, 300 MHz) δ 7.69 yellowmin (ddd, 2 H, J = 2.0, 2.7, 8.7), 7.47 (dd, solid Method A 2 H, J =2.0, 8.7), 7.15 (dd, 1 H, J = 2.1, 12.0), 7.03 (d, 1 H, J = 8.4), 6.84(t, 1 H, J = 8.5), 6.30 (br s, 1 H), 5.25- 5.30 (m, 2 H), 4.96 (d, 1 H,J = 1.4), 4.87 (td, 1 H, J = 1.4, 9.9), 4.57 (d, 1 H, J = 15.4),4.23-4.32 (m, 2 H), 3.87 (s, 3 H), 2.60-2.67 (m, 1 H), 2.15-2.24 (m, 1H). 74 1-Method A colorless 436.92 1.88 437.09 ¹H NMR (CDCl₃, 300 MHz) δ7.97 oil min (dd, 2 H, J = 1.7, 8.3), 7.71 (dd, 2 H, J = Method A 2.0,8.7), 7.43-7.50 (m, 4 H), 6.26 (br s, 1 H), 5.22-5.35 (m, 1 H), 5.18 (brs, 1 H), 4.84-4.96 (m, 2 H), 4.69 (d, 1 H, J = 15.8), 4.41 (d, 1 H, J =15.8), 4.31 (t, 1 H, J = 7.5), 3.91 (s, 3 H), 2.60-2.67 (m, 1 H),2.11-2.24 (m, 1 H). 75 1-Method A white 403.89 1.63 404.03 ¹H NMR(CDCl₃, 300 MHz) δ 7.71 solid min (ddd, 2 H, J = 2.0, 2.6, 8.7), 7.60(dd, Method A 2 H, J = 1.9, 8.3), 7.49-7.52 (m, 4 H), 6.21 (br s, 1 H),5.22-5.33 (m, 1 H), 5.17 (br s, 1 H), 4.88-4.98 (m, 2 H), 4.71 (d, 1 H,J = 16.2), 4.40 (d, 1 H, J = 16.1), 4.32 (t, 1 H, J = 7.6), 2.54- 2.63(m, 1 H), 2.09-2.19 (m, 1 H). 76 1-Method A white 446.88 2.04 447.05 ¹HNMR (CDCl₃, 300 MHz) δ 7.67 solid min (d, 2 H, J = 8.6), 7.45-7.56 (m, 6H), Method A 6.24 (br s, 1 H), 5.25-5.39 (m, 1 H), 5.19 (br s, 1 H),4.88-4.98 (m, 2 H), 4.68 (d, 1 H, J = 15.8), 4.42 (d, 1 H, J = 15.81),4.34 (t, 1 H, J = 7.5), 2.58- 2.68 (m, 1 H), 2.13-2.23 (m, 1 H). 771-Method A white 405.91 1.51 406.2 ¹H NMR (CDCl₃, 300 MHz) δ 7.70 (d, 2H, solid min J = 8.0 Hz) 7.68 (d, 2 H, J = 8.0 Hz), Method B 7.47-7.51(m, 4 H), 6.15 (s, br, 1 H), 5.16 (s, br, 1 H), 4.53 (dd, 2 H, J = 50Hz, 15 Hz), 4.21-4.26 (m, 1 H), 1.82-1.87 (m, 1 H), 1.20-1.25 (m, 1H),0.97-1.09 (m, 2 H), 0.74 (t, 3 H, J = 7.0 Hz). 78 1-solid white 408.951.84 431.04 ¹H NMR (CDCl₃) δ 7.83 (d, 2 H, support foam min M + Na J =8.0 Hz), 7.52 (d, 2 H, J = 8.0 Hz), Method B 7.34-7.45 (m, 5 H), 5.85(s, br, 2 H), 5.17 (q, 1 H, 7.2 Hz), 3.78 (dd, 1 H, J = 8.4 Hz, 4 Hz),2.36 (m, 1 H), 1.62 (m, 1 H), 1.50 (d, 3 H, J = 7.2 Hz), 1.23 (m, 1 H),0.91 (d, 3 H, J = 6.6 Hz), 0.84 (d, 3 H, J = 6.6 Hz) 79 1-solidcolorless 408.95 1.89 431.04 ¹H NMR (CDCl₃) δ 7.77 (d, 2 H, supportsyrup Method B M − Na J = 8.0 Hz), 7.50 (d, 2 H, J = 8.0 Hz), 7.17-7.32(m, 5 H), 6.67 (s, br, 1 H), 6.15 (s, br, 1 H), 5.17 (q, 1 H, 7.2 Hz),4.26 (dd 1 H, J = 6.6 Hz), 3.48 (m, 1 H), 3.37 (m, 1 H), 2.97 (m, 1 H),2.90 (m, 1 H), 1.92 (m, 1 H), 1.33 (m, 1 H), 1.10 (m, 1 H), 0.76 (d, 3H, J = 6.6 Hz), 0.75 (d, 3 H, J = 6.6 Hz) 80 1-solid yellow 430.36 1.64430.02 ¹H NMR (CDCl₃) δ 8.34 (s, 1 H, support solid min 7.67 (d, 1 H, J= 6.8 Hz), 7.48 (d, 1 H, Method B 6.8 Hz), 7.25 (d, 1 H, J = 6.8 Hz),6.1 (br. S, 1 H), 5.29 (br. s, 1 H), 4.59 (d, 1 H, J = 16 Hz), 4.39 (d,1 H), J = 16 Hz), 1.8 (m, 1 H), 1.32 (m, 1 H), 1.06 (m, 1 H), 0.78 (d, 3H, J = 64 Hz), 0.68 (d, 3 H, J = 6.4 Hz) 81 1-solid white 435.39 1.87456.92 ¹H NMR (CDCl₃) δ 7.64 (d, 2 H, support solid Method B M + Na J =8.0 Hz), 7.50 (d, 2 H, J = 8.0 Hz), 6.79 (d, 1 H, J = 3.7 Hz), 6.72 (d,1 H, J = 3.7 Hz), 4.60 (d, 1 H, J = 21.9), 4.56 (d, 1 H, J = 21.9 Hz),4.28 (t, 1 H, J = 7.4 Hz), 1.86 (m, 1 H), 1.33 (m, 1 H), 1.25 (m, 1 H),0.76 (d, 3 H, J = 6.5 Hz), 0.73 (d, 3 H, J = 6.5 Hz) 82 1-Method A white420.96 1.97 421.2 ¹H NMR (CDCl₃, 500 MHz) δ 7.77 solid Method A (d, 2 H,J = 8.6), 7.45 (d, 2 H, J = 9.10), 7.26-7.35 (m, 5 H), 6.54 (d, 1 H, J =16), 6.38 (br s, 1 H), 6.00- 6.07 (m, 1 H), 5.34 (br s, 1 H), 4.36 (t, 1H, J = 7.2), 4.02-4.15 (m, 2 H), 1.83-1.92 (m, 1 H), 1.35-1.43 (m, 1 H),1.25-1.32 (m, 1 H), 0.79 (d, 3 H, J = 6.7), 0.77 (d, 3 H, J = 6.7). 83 5white 389.90 1.91 390.2 ¹H NMR (DMSO-d₆, 500 MHz) δ solid Method D 8.08(br s, 1 H), 7.97 (d, 2 H, J = 8.7), 7.65 (d, 2 H, J = 8.5), 7.01 (br s,1 H), 4.46 (d, 1 H, J = 18), 4.22 (d, 1 H, J = 18), 3.91 (t, 1 H, J =6.3), 3.00 (s, 3 H), 2.85 (s, 3 H), 1.40-1.50 (m, 2 H), 1.30-1.40 (m, 1H), 0.85 (d, 3 H, J = 6.1), 0.64 (d, 3 H, J = 6.0). 84 5 white 375.881.38 276.0 ¹H NMR (CDCl₃, 500 MHz) δ 7.85 solid Method A (dd, 2 H, J =1.8, 6.8), 7.50 (dd, 2 H, J = 2.0, 6.8), 7.40 (br s, 1 H), 6.37 (br s, 1H), 5.25 (br s 1 H), 4.26 (dd, 1 H, J = 6.2, 8.6), 3.97 (d, 1 H, J =17), 3.85 (d, 1 H, J = 17), 2.85 (d, 3 H, J = 4.8), 1.75-1.85 (m, 1 H),1.40-1.48 (m, 1 H), 0.88 (d, 3 H, J = 6.4), 0.87 (d, 3 H, J = 6.6). 85 5white 448.01 2.18 448.1 ¹H NMR (CDCl₃, 500 MHz) δ 8.10 solid Method C(br s, 1 H), 7.92 (d, 2 H, J = 8.5), 7.50 (d, 2 H, J = 8.5), 5.18 (br s,1 H), 4.35 (d, 1 H, J = 17), 4.15 (t, 1 H, J = 7.4), 3.97-4.05 (m, 1 H),3.95 (d, 1 H, J = 17), 3.70-3.89 (m, 3 H), 2.55-2.85 (m, 4 H), 1.85-1.91(m, 1 H), 1.55-1.85 (m, 1 H), 1.30-1.40 (m, 1 H), 0.85 (d, 3 H, J =6.4), 0.83 (d, 3 H, J = 6.4). 86 5 white 429.97 2.26 430.2 ¹H NMR(CDCl₃, 500 MHz) δ 8.59 solid Method C (br s, 1 H), 7.92 (d, 2 H, J =9.1), 7.47 (d, 2 H, J = 8.6), 5.16 (br s, 1 H), 4.42 (d, 1 H, J = 17),4.23 (dd, 1 H, J = 5.6, 8.6), 3.87 (d, 1 H, J = 17), 3.55-3.65 (m, 1 H),3.40-3.52 (m, 3 H, 1.80- 2.00 (m, 1 H), 1.45-1.80 (m, 7 H), 1.35-1.45(m, 1 H), 0.89 (d, 3 H, J = 6.7), 0.86 (d, 3 H, J = 6.5). 87 5 white437.95 2.37 438.2 ¹H NMR (CDCl₃, 500 MHz) δ 8.95 solid Method C (br s, 1H), 7.83 (d, 2 H, J = 8.6), 7.47 (d, 2 H, J = 8.1), 7.43 (d, 2 H, J =8.6), 7.33 (t, 2 H, J = 8.1), 7.13 (t, 1 H, J = 7.6), 6.65 (br s, 1 H),5.45 (br s, 1 H), 4.40 (dd, 1 H, J = 6.1, 8.6), 4.07 (d, 1 H, J = 17),4.03 (d, 1 H, J = 17), 1.70-1.80 (m, 1 H), 1.55-1.65 (m, 2 H), 0.93 (d,3 H, J = 7.0), 0.90 (d, 3 H, 6.4). 88 5 white 401.92 1.94 402.2 ¹H NMR(CDCl₃, 500 MHz) δ 7.85 solid Method C (dd, 2 H, J = 1.9, 8.9), 7.50(dd, 2 H), J = 2.0, 8.7), 7.40 (br s, 1 H), 6.55 (br s, 1 H), 6.30 (brs, 1 H), 4.23 (dd, 1 H, J = 2.9, 8.9), 3.92 (d, 1 H, J = 17), 3.83 (d, 1H, J = 17), 2.68-2.73 (m, 1 H), 1.75-1.83 (m, 1 H), 1.50-1.57 (m, 1 H),1.40-1.49 (m, 1 H), 0.88 (d, 3 H, J = 6.4), 0.87 (d, 3 H, J = 6.7), 0.80(d, 2 H, J = 7.0), 0.51 (t, 2 H, J = 4.0). 89 6 white 438.93 1.67 439.17¹H NMR (CDCl₃, 300 MHz) δ 7.91 solid min (d, 2 H, J = 8.2), 7.81-7.84(m, 3 H) Method A 7.56 (d, 2 H, J = 8.6), 7.49 (d, 2 H, J = 8.2), 6.55(br s, 1 H), 5.10 (d, 1 H, J = 15.4), 4.23 (dd, 1 H, J = 15.4),2.04-2.14 (m, 1 H), 1.20-1.31 (m, 1 H), 0.80-0.89 (m, 1 H), 0.74 (d, 3H, J = 6.6), 0.68 (d, 3 H, J = 6.6). 90 6 white 422.89 1.41 423.05 ¹HNMR (dmso-d₆, 300 MHz) δ 7.86 solid min (d, 2 H, J = 8.2), 7.85 (br s, 1H), 7.81 Method A (d, 2 H, J = 8.6), 7.61 (d, 2 H, J = 8.6), 7.47 (d, 2H, J = 8.0), 7.10 (br s, 1 H), 5.45-5.55 (m, 1 H), 4.83-4.95 (m, 3 H),4.71 (d, 1 H, J = 17.0), 4.47 (t, 1 H, J = 7.4), 2.29-2.37 (m, 1 H),2.13-2.22 (m, 1 H). 91 2 tan 450.0 1.62 450.2 ¹H NMR (CDCl₃) δ 7.67 (d,2 H, solid min J = 7.0 Hz) 7.42 (d, 2 H, J = 7.0 Hz), Method B 7.17-7.26(m, 2 H), 6.49-6.58 (m, 2 H), 6.18 (s, br, 1 H), 5.11 (s, br, 1 H), 4.33(dd, 2 H, J = 50 Hz, 15 Hz), 4.12-4.20 (m, 1 H), 3.21-3.30 (m, 4 H),1.91-2.04 (m, 5 H), 1.32-1.38 (m, 1 H), 0.94-1.09 (m, 2 H), 0.75 (t, 3H, J = 8.0 Hz). 92 7 white 502.08 1.72 502.1 ¹H NMR (DMSO-d₆, 500 MHz) δsolid Method A 7.86 (dd, 2 H, J = 2.0, 6.8), 7.65 (dd, 2 H, J = 2.0,6.8) 7.37 (br s, 1 H), 7.07 (br s, 1 H), 4.19 (t, 1 H, J = 7.6), 3.92(br s, 2 H), 3.35 (dd, 1 H, J = 15, 6.8), 3.05 (dd, 1 H, J = 15, 8.1),1.85 (br s, 1 H), 1.50-1.70 (m, 4 H), 1.38 (s, 9 H), 1.10-1.20 (m, 1 H),0.80-1.00 (m, 3 H), 0.82 (d, 6 H, J = 7.6). 93 5 white 478.01 1.60 478.1¹H NMR (DMSO-d₆, 500 MHz) δ solid Method A 8.05 (s, 1 H), 7.98 (d, 2 H,J = 7.8), 7.65 (d, 2 H, J = 7.8), 7.05 (s, 1 H), 4.73 (s, 1 H),4.55-4.65 (m, 2 H), 4.37 (t, 1 H, J = 16), 3.95 (br s, 1 H), 3.70 (br s,2 H), 2.90 (br s, 1 H), 2.77 (br s, 1 H), 1.00-1.55 (m, 4 H), 0.70 (d, 6H, J = 4.1). 94 5 white 530.20 1.59 531.2 ¹H NMR (DMSO-d₆, 500 MHz) δsolid Method A 7.96 (d, 2 H, J = 8.7), 7.65 (d, 2 H, 8.6), 7.02 (s, 1H), 4.5 (d, 1 H, J = 18), 4.27 (d, 2 H, J = 18), 3.95 (br s, 1 H).3.35-3.50 (m, 8 H), 1.30-1.55 (m, 3 H), 1.41 (s, 9 H), 0.74 (d, 3 H, J =6.5) 0.66 (d, 3 H, J = 6.0). 95 8 white 424.95 1.49 425.17 ¹H NMR, 500Hz, (CDCl₃) δ 7.68 (d, solid min 2 H, J = 8.0 Hz), 7.46 (d, 2 H, J = 8.0Hz), Method A 7.33 (d, 2 H, J = 8.0 Hz), 7.28 (d, 2 H, J = 8.0 Hz), 6.26(s, br, 1 H), 5.35 (s, br, 1 H), 4.67 (s, br, 2 H), 4.56 (d, 1 H, J_(ab)= 16 Hz), 4.36 (d, 1 H, J_(ab) = 16 Hz), 4.26 (t, 1 H, J = 7.6 Hz),1.86-1.80 (m, 2 H), 1.34-1.28 (m, 1 H), 1.16-1.10 (m, 1 H), 0.96 (d, 3H, J = 7.0 Hz), 0.93 (d, 3 H, J = 7.0 Hz) 96 1-Method A white 452.961.75 453.1 ¹H NMR (CDCl₃) δ solid min 7.96-7.90 (m, 2 H), 7.64 (A ofABq, Method A 2 H, J = 8.8 Hz), 7.56 (d, 1 H, J = 7.5 Hz), 7.43 (B ofABq, 2 H, J = 8.8 Hz), 7.37 (t, 1 H, J = 7.5 Hz), 6.28 (bs, 1 H), 5.25(bs, 1 H), 4.61 (A of ABq, 1 H, J = 15.7 Hz, ), 4.48 (B of ABq, 1 H, J =15.7 Hz), 4.36 (t, 1 H, J = 7.3 Hz), 3.91 (s, 3 H), 1.86-1.76 (m, 1 H),1.39-1.30 (m, 1 H), 1.23-1.13 (m, 1 H), 0.78 (d, 3 H, J = 6.6 Hz), 0.68(d, 3 H, J = 6.6 Hz). 97 1-Method A white 471.92 1.53 418.11 ¹H NMR(CDCl₃, 300 MHz) δ 7.71 solid min (d, 2 H, J = 8.7), 7.60 (d, 2 H, J =8.4), Method A 7.47-7.51 (m, 4 H), 6.28 (br s, 1 H), 5.17 (br s, 1 H),4.73 (d, 1 H, J = 16.2), 4.41 (d, 1 H, J = 15.9), 4.32 (dd, 1 H, J =1.5, 8.1), 1.65-1.82 (m, 1 H), 1.14-1.30 (m, 1 H), 0.27-0.40 (m, 2 H),0.12-0.22 (m, 1 H), −0.18- 0.05 (m, 2 H). 98 1-Method A white 460.911.76 461.05 ¹H NMR (CDCl₃, 300 MHz) δ 7.67 solid min (d, 2 H, J = 8.4),7.44-7.56 (m, 6 H), Method A 6.32 (br s, 1 H), 5.20 (br s, 1 H), 4.70(d, 1 H, J = 15.6), 4.43 (d, 1 H, J = 15.6), 4.35 (t, 1 H, J = 7.8),1.70-1.84 (m, 1 H), 1.26-1.32 (m, 1 H), 0.32- 0.40 (m, 2 H), 0.16-0.24(m, 1 H), −0.14-0.00 (m, 2 H). 99 1-Method A white 450.94 1.63 451.06 ¹HNMR (CDCl₃, 300 MHz) δ 7.97 solid min (d, 2 H, J = 8.3), 7.70 (d, 2 H, J= 8.7), Method A 7.43-7.48 (m, 4 H), 6.32 (br s, 1 H), 5.15 (br s, 1 H),4.70 (d, 1 H, J = 15.8), 4.43 (d, 1 H, J = 15.8), 4.35 (t, 1 H, J =7.8), 3.91 (s, 3 H), 1.70-1.82 (m, 1 H), 1.23-1.35 (m, 1 H), 0.32- 0.40(m, 2 H), 0.10-0.21 (m, 1 H), −0.25-−0.05 (m, 2 H). 100 1-Method A white509.06 1.94 509.2 ¹H NMR (CDCl₃) δ 7.58 (A of ABq, solid min 2 H, J =8.8 Hz), 7.40 (B of ABq, 2 H, Method A J = 8.8 Hz), 7.24 (bs, 4 H), 6.20(bs, 1 H), 5.23 (bs, 1 H), 4.45 (s, 2 H), 4.36 (t, 1 H, J = 7.3 Hz),4.12 (q, 2 H, J = 7.2 Hz), 1.83-1.74 (m, 1 H), 1.55 (s, 3 H), 1.55 (s, 3H), 1.39-1.20 (m, 2 H), 1.19 (t, 3 H, J = 7.2 Hz), 0.78 (d, 3 H, J = 6.6Hz), 0.66 (d, 3 H, J = 6.6 Hz). 101 6 white 508.04 1.48 508.22 ¹H NMR(CDCl₃, 300 MHz) δ 7.68 solid min (d, 2 H, J = 8.6), 7.29-7.47 (m, 6 H),Method A 6.38 (br s, 1 H), 5.75 (br s, 1 H), 4.65 (d, 1 H, J = 16.0),4.42 (d, 1 H, J = 16.0), 4.32 (t, 1 H, J = 7.5), 3.30-3.85 (br m, 8 H),1.69-1.78 (m, 1 H), 1.28- 1.37 (m, 1 H), 1.08-1.14 (m, 1 H), 0.76 (d, 3H, J = 6.5), 0.63 (d, 3 H, J = 6.6). 102 6 white 491.59 1.39 492.23 ¹HNMR (CDCl₃, 300 MHz) δ 7.75- solid min 7.80 (m, 2 H), 7.42 (d, 2 H, J =8.2), Method A 7.33 (d, 2 H, J = 8.2), 7.14-7.20 (m, 2 H), 6.37 (br s, 1H), 5.64 (br s, 1 H), 4.64 (d, 1 H, J = 16.0), 4.44 (d, 1 H, J = 16.0),4.31 (t, 1 H, J = 7.1), 3.20- 3.85 (br m, 8 H), 1.70-1.78 (m, 1 H),1.28-1.35 (m, 1 H), 1.05-1.14 (m, 1 H), 0.76 (d, 3 H, J = 6.5), 0.63 (d,3 H, J = 6.6). 103 6 colorless 551.11 1.32 551.24 ¹H NMR (CDCl₃, 300MHz) δ 7.67- oil min 7.72 (m, 4 H), 7.42-7.48 (m, 4 H), Method A 6.82(br s, 1 H), 6.25 (br s, 1 H), 5.31 (br s, 1 H), 4.65 (d, 1 H, J =15.9), 4.43 (d, 1 H, J = 15.9), 4.30 (t, 1 H, J = 7.9), 3.70-3.79 (m, 4H), 3.53-3.59 (m, 2 H), 2.53-2.65 (m, 6 H), 1.79- 1.86 (m, 1 H),1.29-1.38 (m, 1 H), 1.08-1.14 (m, 1 H), 0.76 (d, 3 H, J = 6.5), 0.65 (d,3 H, J = 6.6). 104 6 white 534.66 1.22 535.28 ¹H NMR (CDCl₃, 300 MHz) δ7.75- solid min 7.80 (m, 2 H), 7.71 (d, 2 H, J = 8.2), Method A 7.43 (d,2 H, J = 8.1), 7.14-7.20 (m, 2 H), 6.81 (br s, 1 H), 6.28 (br s, 1 H),5.31 (br s, 1 H), 4.64 (d, 1 H, J = 15.9), 4.44 (d, 1 H, J = 15.9), 4.29(t, 1 H, J = 7.6), 3.70-3.79 (m, 4 H), 3.53-3.59 (m, 2 H), 2.52-2.63 (m,6 H), 1.77-1.85 (m, 1 H), 1.29-1.38 (m, 1 H), 1.06-1.13 (m, 1 H), 0.75(d, 3 H, J = 6.5), 0.65 (d, 3 H, J = 6.6). 105 6 white 607.17 1.70607.29 ¹H NMR (CDCl₃, 300 MHz) δ 7.69 solid min (d, 2 H, J = 8.6),7.30-7.47 (m, 6 H), Method A 6.38 (br s, 1 H), 5.75 (br s, 1 H), 4.65(d, 1 H, J = 16.0), 4.43 (d, 1 H, J = 16.0), 4.33 (t, 1 H, J = 7.5),3.30-3.85 (br m, 8 H), 1.72-1.79 (m, 1 H), 1.45 (s, 9 H), 1.24-1.39 (m,1 H), 1.05-1.18 (m, 1 H), 0.76 (d, 3 H, J = 6.5), 0.62 (d, 3 H, J =6.6). 106 6 white 554.11 1.75 554.19 ¹H NMR (CDCl₃, 300 MHz) δ 7.70solid min (ddd, 2 H, J = 1.9, 2.4, 8.6), 7.47 Method A (ddd, 2 H, J =2.0, 2.3, 8.7), 7.37-7.42 (m, 4 H), 7.15-7.20 (m, 4 H), 6.31 (br s, 1H), 5.60 (br s, 1 H), 4.87 (br s, 1 H), 4.65 (d, 1 H, J = 15.9), 4.52(br s, 1 H), 4.47 (d, 1 H, J = 15.9), 4.33 (t, 1 H, J = 7.2), 4.05 (brs, 1 H), 3.61 (br s, 1 H), 2.85-3.01 (br m, 2 H), 1.72- 1.85 (m, 1 H),1.30-1.42 (m, 1 H), 1.08-1.18 (m, 1 H), 0.79 (d, 3 H, J = 6.5), 0.66 (d,3 H, J = 6.6). 107 1-Method A clear 456.97 1.60 455.1 ¹H NMR (CDCl₃) δ7.61 (d, 2 H, wax min (M − H⁻) J = 8.0 Hz) 7.43 (d, 2 H, J = 8.0 Hz),Method B 6.82-7.10 (m, 3 H), 6.21 (s, br, 1 H), 5.15 (s, br, 1 H), 4.35(dd, 2 H, J = 50 Hz, 15 Hz), 4.15-4.22 (m, 1 H), 3.89 (s, br, 3 H),2.30-2.33 (m, 1 H), 0.86-0.98 (m, 1 H), 0.74 (s, 9 H). 108 1-Method Awhite 433.96 1.58 432.14 ¹H NMR (CDCl₃) δ 7.67 (d, 2 H, solid min (M −H⁻) J = 8.0 Hz), 7.58 (d, 2 H, J = 8.0 Hz), Method B 7.45-7.49 (m, 4 H),6.19 (s, br, 1 H), 5.15 (s, br, 1 H), 4.55 (dd, 2 H, J = 50 Hz, 15 Hz),4.20-4.24 (m, 1 H), 2.25-2.31 (m, 1 H), 0.84-0.88 (m, 1 H), 0.74 (s, 9H). 109 1-Method A white 476.95 1.62 475.12 ¹H NMR (CDCl₃) δ 7.61 (d, 2H, solid min (M − H⁻) J = 8.0 Hz) 7.51 (d, 2 H, J = 8.0 Hz), Method B7.40-7.44 (m, 4 H), 6.20 (s, br, 1 H), 5.21 (s, br, 1 H), 4.51 (dd, 2 H,J = 50 Hz, 15 Hz), 4.24-4.28 (m, 1 H), 2.28-2.32 (m, 1 H), 0.91-0.96 (m,1 H), 0.76 (s, 9 H). 110 8 tan 452.02 1.25 452.23 ¹H NMR, 400 Hz,(CDCl₃) δ 7.94 (d, solid min 2 H, J = 8.0 Hz), 7.74 (d, 2 H, J = 8.0Hz), Method A 7.63 (d, 2 H, J = 8.0 Hz), 7.38 (d, 2 H, J = 8.0 Hz), 6.27(s, br, 1 H), 5.40 (s, br, 1 H), 4.52 (d, 1 H, J_(ab) = 16 Hz), 4.44 (d,1 H, J_(ab) = 16 Hz), 3.28-3.23 (m, 3 H), 2.17 (s, br, 6 H), 1.95 (m, 1H), 1.55 (m, 2 H), 0.96 (d, 3 H, J = 7.0 Hz), 0.93 (d, 3 H, J = 7.0 Hz)111 5 white 535.97 2.65 536.04 ¹H NMR (CDCl₃, 400 MHz) δ 7.80 solid min(dd, 2 H, J = 2.0, 9.0), 7.45 (dd, 2 H, J = Method C 2.0, 9.0), 7.32(dd, 2 H, J = 1.8, 9.0), 7.24 (br s, 1 H), 7.17 (d, 2 H, J = 9.0), 5.50(br s, 1 H), 4.43 (qd, 2 H, J = 6.0, 15), 4.22 (t, 1 H, J = 7.0), 4.05(d, 1 H, J = 17), 3.90 (d, 1 H, J = 17), 1.70-1.80 (m, 1 H), 1.42-1.55(m, 1 H), 1.32-1.41 (m, 1 H), 0.83 (d, 6 H, J = 7.9). 112 5 white 487.931.52 488.20 ¹H NMR (CDCl₃, 400 MHz) δ 7.77 foam min (d, 2 H, J = 8.3),7.45 (d, 2 H, J = Method A 9.0), 7.30 (br s, 1 H), 7.05-7.10 (m, 1 H),6.90-7.05 (m, 2 H), 5.53 (br s, 1 H), 4.39-4.50 (m, 2 H), 4.24 (t, 1 H,J = 7.1), 4.02 (d, 1 H, J = 17), 3.90 (d, 2 H, J = 17), 1.70-1.80 (m, 1H), 1.42- 1.55 (m, 1 H), 1.35-1.42 (m, 1 H), 0.83 (d, 6 H, J = 7.7). 1135 white 417.96 1.52 418.23 ¹H NMR (CDCl₃, 400 MHz) δ 7.92 oily min (brs, 1 H), 7.82 (d, 2 H, J = 8.2), 7.47 solid Method A (d, 2 H, J = 8.2),7.25 (br s, 1 H), 6.23 (br s, 1 H), 5.47 (br s, 1 H), 4.25 (t, 1 H, J =7.2), 3.91 (d, 1 H, J = 17), 3.75 (d, 1 H, J = 17), 1.75-1.82 (m, 1 H),1.50-1.62 (m, 1 H), 1.38-1.50 (m, 1 H), 1.35 (s, 9 H), 0.89 (d, 3 H, J =5.4), 0.87 (d, 3 H, J = 5.6). 114 5 white 458.02 1.62 458.26 ¹H NMR(CDCl₃, 400 MHz) δ 7.84 solid min (dd, 2 H, J = 2.0, 8.8), 7.68 (br s, 1H), Method A 7.47 (dd, 2 H, 2.0, 8.3), 6.62 (br t, 1 H, J = 5.3), 5.45(br s, 1 H), 4.25 (dd, 1 H, J = 2.3, 6.1), 3.98 (d, 1 H, J = 17), 3.85(d, 1 H, J = 17), 303-3.15 (m, 2 H), 1.86-1.92 (m, 1 H), 1.40- 1.85 (m,7 H), 1.05-1.35 (m, 4 H), 0.90-0.99 (m, 2 H), 0.88 (d, 3 H, J = 6.6),0.87 (d, 3 H, J = 6.4). 115 5 white 452.96 1.14 453.22 ¹H NMR (CDCl₃,400 MHz) δ 8.53 solid min (d, 2 H, J = 5.2), 8.04 (t, 1 H, J = 5.2),Method A 7.80 (dd, 2 H, J = 1.8, 8.5), 7.46 (dd, 2 H, J = 1.8, 8.7),7.33 (br s, 1 H), 7.29 (d, 2 H, J = 5.4), 5.78 (br s, 1 H), 4.47 (qd, 2H, J = 6.0, 16, ), 4.21 (t, 1 H, J = 7.4), 4.07 (d, 1 H, J = 17), 3.92(d, 1 H, J = 17), 1.67-1.77 (m, 1 H), 1.30-1.47 (m, 2 H), 0.81 (d, 3 H,J = 6.5), 0.77 (d, 3 H, J = 7.0). 116 5 white 419.93 1.29 420.23 ¹H NMR(CDCl₃, 400 MHz) δ 7.87 foam Min (dd, 2 H, J = 2.0, 8.5), 7.85 (br s, 1H), Method A 7.49 (dd, 2 H, J = 2.1, 9.0), 6.73 (br s, 1 H), 5.55 (br s,1 H), 4.22 (dd, 1 H, J = 6.1, 8.3), 4.02 (d, 1 H, J = 17), 3.87 (d, 1 H,J = 17), 3.40-3.50 (m, 4 H), 3.36 (s, 3 H), 1.77-1.86 (m, 1 H),1.46-1.57 (m, 1 H), 1.30-1.41 (m, 1 H), 0.84 (d, 3 H, J = 6.7), 0.83 (d,3 H, J = 6.5). 117 5 white 475.01 1.16 475.26 ¹H NMR (CDCl₃, 400 MHz) δ7.85 foam min (dd, 2 H, J = 2.0, 8.5), 7.64 (br s, 1 H), Method A 7.47(dd, 2 H, J = 1.5, 7.1), 6.87 (br s, 1 H), 5.55 (br s, 1 H), 4.22 (dd, 1H, J = 6.2, 7.9), 4.00 (d, 1 H, J = 17), 3.87 (d, 1 H, J = 17), 3.72 (t,1 H, J = 4.2), 3.30-3.45 (m, 2 H), 2.45-2.55 (m, 6 H), 1.75-1.85 (m, 1H), 1.50-1.63 (m, 1 H), 1.30-1.41 (m, 1 H), 0.86 (d, 6 H, J = 9.0). 1181-Method A white 459.79 1.62 461.1 ¹H NMR (CDCl₃) δ 7.67 (d, 2 H, solidmin J = 7.0 Hz) 7.48 (d, 2 H, J = 7.0 Hz), Method B 7.41 (d, 2 H, J =6.5 Hz), 7.21 (d, 2 H, J = 6.5 Hz), 6.21 (s, br, 1 H), 5.20 (s, br, 1H), 4.43 (dd, 2 H, J = 50 Hz, 15 Hz), 4.12-4.24 (m, 1 H), 1.88-1.90 (m,1 H), 1.24-1.29 (m, 1 H), 0.98-1.08 (m, 2 H), 0.74 (t, 3 H, J = 7.0 Hz).119 1-Method A yellow 437.06 1.84 (M + Na)⁺ ¹H NMR (400 MHz, DMSO) δ7.83 solid min 459.9 (d, 2 H, J = 8.8), 7.80 (d, 2 H, J = 8.3), Method F7.64 (d, 2 H, J = 8.5), 7.59 (d, 2 H, J = 8.6), 7.48 (s, 1 H), 7.15 (s,1 H), 4.79 (ABq, 2 H, Δυ = 22.2, J_(ab) = 17.4), 4.44 (dd, 1 H, J = 8.0,6.3), 2.21 (m, 2 H), 1.84 (m, 1 H), 1.81 (s, 3 H), 1.53 (m, 1 H). 1201-Method A white 480.06 2.08 (M + Na)⁺ ¹H NMR (400 MHz, DMSO) δ 7.82solid min 503.0 (d, 2 H, J = 8.8), 7.68 (d, 2 H, J = 8.6), Method F 7.61(m, 4 H), 7.48 (s, 1 H), 7.16 (s, 1 H), 4.80 (ABq, 2 H, , Δυ = 16.7,J_(ab) = 17.0), 4.45 (dd, 1 H, J = 8.2, 6.2), 2.22 (m, 2 H), 1.82 (m, 1H), 1.78 (s, 3 H), 1.61 (m, 1 H). 121 5 white 488.19 1.20 489.26 ¹H NMR(CDCl₃, 400 MHz) δ 7.95 solid min (br s, 1 H), 7.85 (dd, 2 H, J = 2.5,9.2), Method A 7.70 (br s, 1 H), 7.47 (dd, 2 H, 2.0, 8.8), 5.42 (br s, 1H), 4.23 (dd, 1 H, J = 6.3, 8.3), 3.94 (d, 1 H, J = 17), 3.83 (d, 1 H, J= 17), 3.73 (t, 4 H, J = 4.7), 3.39-3.48 (m, 1 H), 3.22-3.33 (m, 1 H),2.42-2.55 (m, 4 H), 1.79-1.88 (m, 2 H), 1.63-1.75 (m, 2 H), 1.49- 1.61(m, 1 H), 1.31-1.45 (m, 1 H), 1.05-1.11 (m, 1 H), 0.88 (d, 6 H, J =6.6). 122 5 white 432.16 1.59 433.12 ¹H NMR (CDCl₃, 400 MHz) δ 8.04solid min (br s, 1 H), 7.88 (dd, 2 H, J = 1.9, 6.9), Method C 7.46 (dd,2 H, J = 1.8, 6.8), 6.93 (br s, 1 H), 5.55 (br s, 1 H), 4.20 (dd, 1 H, J= 6.2, 8.3), 4.01 (d, 1 H, J = 17), 3.80 (d, 1 H, J = 17), 3.25-3.40 (m,2 H), 2.40-2.50 (m, 2 H), 2.25 (s, 6 H), 1.75-1.90 (m, 1 H), 1.45-1.60(m, 1 H), 1.30-1.45 (m, 1 H), 0.84 (d, 3 H, J = 6.1), 0.82 (d, 3 H, J =6.4). 123 6 white 466.0 1.49 466.17 ¹H NMR (CDCl₃, 500 MHz) δ 7.68 solidmin (d, 4 H, J = 8.6), 7.47 (ddd, 2 H, J = Method A 1.6, 2.4, 8.6), 7.41(d, 2 H, J = 8.2), 6.25 (br s, 1 H), 6.12 (br s, 1 H), 5.30 (br s, 1 H),4.63 (d, 1 H, J = 15.8), 4.44 (d, 1 H, J = 15.8), 4.30 (t, 1 H, J =6.8), 3.47-3.52 (m, 2 H), 1.78-1.84 (m, 1 H), 1.30-1.34 (m, 1 H), 1.25(t, 3 H), J = 7.2), 1.08-1.13 (m, 1 H), 0.76 (d, 3 H, J = 6.6), 0.65 (d,3 H, J = 6.6). 124 6 colorless 546.05 1.65 546.19 ¹H NMR (CDCl₃, 500MHz) δ 7.71 oil min (d, 2 H, J = 8.2), 7.67 (d, 2 H, J = 8.6), Method A7.46 (d, 2 H, J = 8.6), 7.41 (d, 2 H, J = 8.0), 6.52 (br s, 1 H), 6.24(br s, 1 H), 5.40 (br s, 1 H), 4.63 (d, 1 H, J = 15.9), 4.59 (d, 2 H, J= 5.6), 4.42 (d, 1 H, J = 15.9), 4.29 (t, 1 H, J = 6.6), 1.78-1.84 (m, 1H), 1.29-1.34 (m, 1 H), 1.25 (t, 3 H), J = 7.2), 1.06-1.11 (m, 1 H),0.76 (d, 3 H, J = 6.6), 0.66 (d, 3 H, J = 6.6). 125 6 colorless 494.061.67 494.24 ¹H NMR (CDCl₃, 500 MHz) δ 7.68 oil min (dd, 2 H, J = 1.7,8.6), 7.63 (d, 2 H, J = Method A 8.2), 7.46 (d, 2 H, J = 8.6), 7.39 (d,2 H, J = 8.2), 6.28 (br s, 1 H), 5.94 (br s, 1 H), 5.35 (br s, 1 H),4.63 (d, 1 H, J = 15.8), 4.41 (d, 1 H, J = 15.8), 4.29 (t, 1 H, J =6.6), 1.78-1.84 (m, 1 H), 1.46 (s, 9 H), 1.29-1.34 (m, 1 H), 1.25 (t, 3H), J = 7.2), 1.06-1.11 (m, 1 H), 0.76 (d, 3 H, J = 6.6), 0.66 (d, 3 H,J = 6.6). 126 7 white 401.15 1.34 402.15 ¹H NMR (DMSO-d₆, 500 MHz), δsolid min 7.87 (d, 2 H, J = 8.5), 7.66 (d, 2 H, J = Method A 8.6), 7.41(s, 1 H), 7.04 (s, 1 H), 4.17 (t, 1 H, J = 7.3), 3.40-3.50 (m, 1 H),3.20-3.25 (m, 1 H), 3.03-3.10 (m, 1 H), 2.65-2.80 (m, 2 H), 1.85-2.00(m, 1 H), 1.20-1.85 (m, 2 H), 1.45- 1.60 (m, 1 H), 1.30-1.40 (m, 1 H),1.10-1.30 (m, 4 H), 0.75-0.90 (m, 1 H), 0.82 (d, 3 H, J = 7.3), 0.80 (d,3 H, J = 7.0). 127 8 white 480.07 1.34 480.25 ¹H NMR, 400 Hz, (CDCl₃) δ7.72 (d, solid min 2 H, J = 8.0 Hz), 7.60 (d, 2 H, J = 8.0 Hz), Method A7.39-7.33 (m, 4 H), 6.26 (s, br, 1 H), 5.40 (s, br, 1 H), 4.53 (d, 1 H,J_(ab) = 16 Hz), 4.42 (d, 1 H, J_(ab) = 16 Hz), 2.58 (q, 4 H, J = 8.0Hz), 1.94 (m, 1 H), 1.59 (m, 2 H), 1.06 (t, 6 H, J = 8.0 Hz), 0.97 (d, 3H, J = 7.0 Hz), 0.94 (d, 3 H, J = 7.0 Hz) 128 8 white 504.1 1.32 504.25¹H NMR, 400 Hz, (CDCl₃) δ 7.69 (d, solid min 2 H, J = 8.0 Hz), 7.73 (d,2 H, J = 8.0 Hz), Method A 7.48 (d, 2 H, J = 8.0 Hz), 7.35 (d, 2 H, J =8.0 Hz), 6.25 (s, br, 1 H), 5.35 (s, br, 1 H), 4.52 (d, 1 H, J_(ab) = 16Hz), 4.44 (d, 1 H, J_(ab) = 16 Hz), 3.35 (s, 2 H), 3.47-3.42 (m, 1 H),3.01 (s, br, 1 H), 1.90 (m, 1 H), 1.63 (m, 2 H) 0.97 (d, 3 H, J = 7.0Hz), 0.94 (d, 3 H, J = 7.0 Hz) 129 8 white 583.2 1.26 583.40 ¹H NMR, 400Hz, (CDCl₃) δ 7.72 (d, solid min 2 H, J = 8.0 Hz), 7.64 (d, 2 H, J = 8.0Hz), Method A 7.37 (m, 4 H), 7.21 (m, 5 H), 6.35 (s, br, 1 H), 5.87 (s,br, 1 H), 4.72 (d, 1 H, J_(ab) = 16 Hz), 4.48 (d, 1 H, J_(ab) = 16 Hz),3.55 (s, 3 H), 3.52 (s, 3 H), 3.74-3.43 (m, 1 H), 2.45 (m, 8 H), 1.59(m, 2 H), 0.98 (d, 3 H, J = 7.0 Hz), 0.95 (d, 3 H, J = 7.0 Hz) 130 8amber 496.06 1.32 496.25 ¹H NMR, 400 Hz, (CDCl₃) δ 7.68 (d, glass min 2H, J = 8.0 Hz), 7.72 (d, 2 H, J = 8.0 Hz), Method A 7.40-7.36 (m, 4 H),6.35 (s, br, 1 H), 5.37 (s, br, 1 H), 4.59 (d, 1 H, J_(ab) = 16 Hz),4.37 (d, 1 H, J_(ab) = 16 Hz), 3.7-3.5 (m, 4 H), 3.48 (s, 3 H), 3.46 (m,1 H), 2.23-2.1 (m, 4 H), 1.85 (m, 1 H), 1.55 (m, 2 H), 0.98 (d, 3 H, J =7.0 Hz), 0.95 (d, 3 H, J = 7.0 Hz) 131 8 amber 510.12 1.33 510.23 ¹HNMR, 400 Hz, (CDCl₃) δ 7.69 (d, oil min 2 H, J = 8.0 Hz), 7.65 (s, b, 4H), 7.37 Method A (d, 2 H, J = 8.0 Hz), 6.25 (s, b, 1 H), 5.36 (s, b, 1H), 4.60 (d, 1 H, J_(ab) = 16 Hz), 4.38 (d, 1 H, J_(ab) = 16 Hz),3.47-3.43 (m, 3 H), 2.61 (m, 4 H), 2.30 (m, 4 H), 1.90 (m, 1 H), 1.59(m, 2 H), 0.96 (d, 3 H, J = 7.0 Hz), 0.94 (d, 3 H, J = 7.0 Hz) 132 8amber 535.15 1.24 535.32 ¹H NMR, 400 Hz, (CDCl₃) δ 8.02 (d, glass min 2H, J = 8.0 Hz), 7.71 (d, 2 H, J = 8.0 Hz), Method A 7.40 (d, 2 H, J =8.0 Hz), 7.36 (d, 2 H, J = 8.0 Hz), 6..27 (s, b, 1 H), 5.40 (s, b, 1 H),4.52 (d, 1 H, J_(ab) = 16 Hz), 4.44 (d, 1 H, J_(ab) = 16 Hz), 3.61 (s, 2H), 3.45 (m, 1 H), 2.72-2.63 (m, 3 H), 2.41 (s, 3 H), 2.32 (s, 3 H),2.05 (t, 4 H, J = 12.0 Hz), 1.90 (m, 3 H), 1.74-1.55 (m, 3 H), 0.96 (d,3 H, J = 7.0 Hz), 0.93 (d, 3 H, J = 7.0 Hz) 133 8 amber 540.13 1.28540.34 ¹H NMR, 400 Hz, (CDCl₃) δ 7.72 (d, glass min 2 H, J = 8.0 Hz),7.70 (d, 2 H, J = 8.0 Hz), Method A 7.52 (d, 2 H, J = 8.0 Hz), 7.38 (d,2 H, J = 8.0 Hz), 7.24-7.14 (m, 3 H), 6.88 (m, 1 H), 6.25 (s, br, 1 H),5.39 (s, br, 1 H), 4.62 (d, 1 H, J_(ab) = 16 Hz), 4.40 (d, 1 H, J_(ab) =16 Hz), 3.45 (s, 2 H), 3.46 (m, 1 H), 3.35-3.19 (m, 2 H), 3.93 (m, 1 H),2.71 (m, 1 H), 2.61 (m, 1 H), 2.49-2.43 (m, 2 H), 1.89 (m, 1 H),1.67-1.54 (m, 2 H), 0.97 (d, 3 H, J = 7.0 Hz), 0.94 (d, 3 H, J = 7.0 Hz)134 8 white 476.04 1.31 476.17 ¹H NMR, 400 Hz, (CDCl₃) δ 7.79 (d, solidmin 2 H, J = 8.0 Hz), 7.65 (d, 2 H, J = 8.0 Hz), Method A 7.47 (d, 2 H,J = 8.0 Hz), 7.37 (d, 2 H, J = 8.0 Hz), 6.35 (s, br, 1 H), 5.85 (s, br,1 H), 4.60 (s, 2 H), 4.76 (d, 1 H, J_(ab) = 16 Hz), 4.30 (d, 1 H, J_(ab)= 16 Hz), 3.72 (s, br, 2 H), 3.46 (m, 1 H), 2.40 (s, br, 3 H), 2.20 (s,1 H), 1.90 (m, 1 H), 1.63 (m, 2 H), 0.98 (d, 3 H, J = 7.0 Hz), 0.95 (d,3 H, J = 7.0 Hz) 135 8 white 532.14 1.34 532.32 ¹H NMR, 400 Hz, (CDCl₃)δ 7.69 (d, solid min 2 H, J = 8.0 Hz), 7.62 (d, 2 H, J = 8.0 Hz), MethodA 7.37 (d, 2 H, J = 8.0 Hz), 7.33 (d, 2 H, J = 8.0 Hz), 6.27 (s, br, 1H), 5.40 (s, br, 1 H), 4.59 (d, 1 H, J_(ab) = 16 Hz), 4.37 (d, 1 H,J_(ab) = 16 Hz), 3.53 (s, 3 H), 3.44 (m, 1 H), 2.79 (t, 2 H, J = 8.0Hz), 2.62 (q, 2 H, J = 8.0 Hz), 2.41 (t, 2 H, J = 8.0 Hz), 2.25 (s, 6H), 1.95-1.85 (m, 1 H), 1.67-1.54 (m, 2 H), 1.07 (t, 3 H, J = 8.0 Hz),0.98 (d, 3 H, J = 7.0 Hz), 0.95 (d, 3 H, J = 7.0 Hz) 136 8 white 537.171.24 537.34 ¹H NMR, 400 Hz, (CDCl₃) δ 7.72 (d, solid min 2 H, J = 8.0Hz), 7.64 (d, 2 H, J = 8.0 Hz), Method A 7.41-7.36 (m, 4 H), 6.57 (s,br, 1 H), 5.40 (s, br, 1 H), 4.59 (d, 1 H, J_(ab) = 16 Hz), 4.37 (d, 1H, J_(ab) = 16 Hz), 3.51 (s, 2 H), 3.45 (m, 1 H), 2.69 (t, 2 H, J = 8.0Hz), 2.62 (t, 2 H, J = 8.0 Hz), 2.55 (q, 4 H, J = 8.0 Hz), 2.35 (s, 3H), 1.89 (m, 1 H), 1.60 (m, 2 H), 1.00 (t, 6 H, J = 8.0 Hz), 0.96 (d, 3H, J = 7.0 Hz), 0.94 (d, 3 H, J = 7.0 Hz) 137 8 white 509.12 1.32 509.33¹H NMR, 400 Hz, (CDCl₃) δ 7.69 (d, solid min 2 H, J = 8.0 Hz), 8.01 (d,2 H, J = 8.0 Hz), Method A 7.64 (d, 2 H, J = 8.0 Hz), 7.40 (d, 2 H, J =8.0 Hz), 7.37 (d, 2 H, J = 8.0 Hz), 6.27 (s, br, 1 H), 5.39 (s, br, 1H), 4.58 (d, 1 H, J_(ab) = 16 Hz), 4.36 (d, 1 H, J_(ab) = 16 Hz), 3.51(s, 2 H), 3.45 (m, 1 H), 2.66 (t, 2 H, J = 8.0 Hz), 2.39 (t, 2 H, J =8.0 Hz), 2.35 (s, 3 H), 2.25 (s, 6 H), 1.90 (m, 1 H), 1.59 (m, 2 H),0.97 (d, 3 H, J = 7.0 Hz), 0.94 (d, 3 H, J = 7.0 Hz) 138 8 clear 494.11.37 494.27 ¹H NMR, 400 Hz, (CDCl₃) δ 7.72 (d, glass min 2 H, J = 8.0Hz), 7.74 (d, 2 H, J = 8.0 Hz), Method A 7.52 (d, 2 H, J = 8.0 Hz), 7.37(d, 2 H, J = 8.0 Hz), 6.26 (s, br, 1 H), 5.39 (s, br, 1 H), 4.55 (d, 1H, J_(ab) = 16 Hz), 4.42 (d, 1 H, J_(ab) = 16 Hz), 3.70 (s, 3 H), 3.46(m, 1 H), 2.38-2.35 (m, 5 H), 1.91 (m, 2 H), 1.60 (m, 2 H), 0.96 (d, 3H, J = 7.0 Hz), 0.90 (d, 3 H, J = 7.0 Hz) 139 8 white 494.1 1.33 494.26¹H NMR, 400 Hz, (CDCl₃) δ 7.63 (d, solid min 2 H, J = 8.0 Hz), 7.73 (d,2 H, J = 8.0 Hz), Method A 7.48 (d, 2 H, J = 8.0 Hz), 7.37 (d, 2 H, J =8.0 Hz), 6.35 (s, br, 1 H), 5.38 (s, br, 1 H), 4.52 (d, 1 H, J_(ab) = 16Hz), 4.44 (d, 1 H, J_(ab) = 16 Hz), 3.47-3.40 (m, 3 H), 2.12 (s, 3 H),1.88 (m, 1 H), 1.60 (m, 2 H), 1.03 (s, 9 H), 0.98 (d, 3 H, J = 7.0 Hz),0.95 (d, 3 H, J = 7.0 Hz) 140 8 amber 521.13 1.27 521.31 ¹H NMR, 400 Hz,(CDCl₃) δ 7.69 (d, glass min 2 H, J = 8.0 Hz), 7.65 (d, 2 H, J = 8.0Hz), Method A 7.39-7.36 (m, 4 H), 6.30 (s, br, 1 H), 5.35 (s, br, 1 H),4.59 (d, 1 H, J_(ab) = 16 Hz), 4.37 (d, 1 H, J_(ab) = 16 Hz), 3.55 (s, 2H), 3.45 (m, 1 H), 2.84 (m, 4 H), 2.48 (q, 2 H, J = 7.0 Hz), 2.28 (m, 4H), 1.88 (m, 1 H), 1.60 (m, 2 H), 1.20 (t, 3 H, J = 7.0 Hz), 0.98 (d, 3H, J = 7.0 Hz), 0.94 (d, 3 H, J = 7.0 Hz) 141 8 white 478.06 1.31 478.22¹H NMR, 400 Hz, (CDCl₃) δ 7.72 (d, solid min 2 H, J = 8.0 Hz), 7.71 (d,2 H, J = 8.0 Hz), Method A 7.48 (d, 2 H, J = 8.0 Hz), 7.38 (d, 2 H, J =8.0 Hz), 6.27 (s, br, 1 H), 5.40 (s, br, 1 H), 4.52 (d, 1 H, J_(ab) = 16Hz), 4.43 (d, 1 H, J_(ab) = 16 Hz), 3.58 (s, br, 2 H), 3.45 (m, 1 H),2.66 (m, 4 H), 1.86 (m, 5 H), 1.60 (m, 2 H), 0.98 (d, 3 H, J = 7.0 Hz),0.95 (d, 3 H, J = 7.0 Hz) 142 8 white 468.02 1.58 468.25 ¹H NMR, 400 Hz,(CDCl₃) δ 7.69 (d, foam min 2 H, J = 8.0 Hz), 7.76 (d, 2 H, J = 8.0 Hz),Method A 7.75 (d, 2 H, J = 8.0 Hz), 7.37 (d, 2 H, J = 8.0 Hz), 6.25 (s,br, 1 H), 5.38 (s, br, 1 H), 4.76 (d, 1 H, J_(ab) = 16 Hz), 4.30 (d, 1H, J_(ab) = 16 Hz), 3.75 (s, 2 H), 3.45 (m, 1 H), 3.36 (s, 3 H), 2.61(s, 3 H), 1.88 (m, 1 H), 1.59 (m, 2 H), 0.98 (d, 3 H, J = 7.0 Hz), 0.95(d, 3 H, J = 7.0 Hz) 143 8 white 482.05 1.28 482.24 ¹H NMR, 400 Hz,(CDCl₃) 7.69 (d, solid min 2 H, J = 8.0 Hz), 7.72 (d, 2 H, J = 8.0 Hz),Method A 7.42-7.36 (m, 4 H), 6.35 (s, br, 1 H), 5.83 (s, br, 1 H), 4.58(d, 1 H, J_(ab) = 16 Hz), 4.39 (d, 1 H, J_(ab) = 16 Hz), 3.52 (s, 1 H),3.50 (s, 2 H), 3.48 (s, 1 H), 3.45 (m, 1 H), 2.55 (t, 2 H, J = 8.0 Hz),2.20 (s, 3 H), 1.90 (m, 1 H), 1.59 (m, 2 H), 0.98 (d, 3 H, J = 7.0 Hz),0.95 (d, 3 H, J = 7.0 Hz) 144 8 clear 512.07 1.22 512.25 ¹H NMR, 400 Hz,(CDCl₃) δ 7.71 (d, glass min 2 H, J = 8.0 Hz), 7.74 (d, 2 H, J = 8.0Hz), Method A 7.39 (d, 2 H, J = 8.0 Hz), 7.31 (d, 2 H, J = 8.0 Hz), 6.27(s, br, 1 H), 5.40 (s, br, 1 H), 4.72 (d, 1 H, J_(ab) = 16 Hz), 4.39 (d,1 H, J_(ab) = 16 Hz), 3.76 (t, 4 H, J = 8.0 Hz), 3.45 (m, 1 H), 3.38 (s,br, 2 H), 3.15 (s, br, 2 H), 3.76 (t, 4 H, J = 8.0 Hz), 1.89 (m, 1 H),1.60 (m, 2 H), 0.98 (d, 3 H, J = 7.0 Hz), 0.95 (d, 3 H, J = 7.0 Hz) 1458 white 492.09 1.31 492.21 ¹H NMR, 400 Hz, (CDCl₃) δ 7.63 (d, solid min2 H, J = 8.0 Hz), 7.71 (d, 2 H, J = 8.0 Hz), Method A 7.47 (d, 2 H, J =8.0 Hz), 7.37 (d, 2 H, J = 8.0 Hz), 6.26 (s, br, 1 H), 5.39 (s, br, 1H), 4.52 (d, 1 H, J_(ab) = 16 Hz), 4.43 (d, 1 H, J_(ab) = 16 Hz),3.47-3.43 (m, 3 H), 2.26 (m, 4 H), 1.89 (m, 2 H), 1.60 (m, 2 H),1.46-1.29 (m, 4 H), 0.97 (d, 3 H, J = 7.0 Hz), 0.94 (d, 3 H, J = 7.0 Hz)146 8 white 564.15 1.33 564.24 ¹H NMR, 400 Hz, (CDCl₃) δ 7.69 (d, solidmin 2 H, J = 8.0 Hz), 7.71 (d, 2 H, J = 8.0 Hz), Method A 7.48 (d, 2 H,J = 8.0 Hz), 7.37 (d, 2 H, J = 8.0 Hz), 6.35 (s, br, 1 H), 5.40 (s, br,1 H), 4.72 (d, 1 H, J_(ab) = 16 Hz), 4.48 (d, 1 H, J_(ab) = 16 Hz), 4.03(q, 2 H, J = 8.0 Hz), 3.47-3.42 (m, 3 H), 3.21 (m, 1 H), 2.62 (m, 1 H),2.63-2.36 (m, 3 H), 2.06-1.95 (m, 1 H), 1.93-1.80 (m, 3 H), 1.67-1.50(m, 3 H), 1.13 (t, 3 H, J = 8.0 Hz), 0.98 (d, 3 H, J = .07 Hz), 0.95 (d,3 H, J = 7.0 Hz) 147 8 white 582.21 1.46 582.41 ¹H NMR, 400 Hz, (CDCl₃)δ 7.69 (d, solid min 2 H, J = 8.0 Hz), 7.71 (d, 2 H, J = 8.0 Hz), MethodA 7.47 (d, 2 H, J = 8.0 Hz), 7.38 (d, 2 H, J = 8.0 Hz), 7.24 (t, 1 H, J= 8.0 Hz), 7.03 (t, 2 H, J = 8.0 Hz), 6.95 (d, 2 H, J = 8.0 Hz), 6.27(s, br, 1 H), 5.40 (s, br, 1 H), 4.52 (d, 1 H, J_(ab) = 16 Hz), 4.44 (d,1 H, J_(ab) = 16 Hz), 3.48-3.43 (m, 3 H), 2.76 (m, 2 H), 2.61 (m, 2 H),1.88 (m, 3 H), 1.69-1.54 (m, 6 H), 1.26 (m, 1 H), 0.98 (d, 3 H, J = 7.0Hz), 0.95 (d, 3 H, J = 7.0 Hz) 148 8 white 570.16 1.41 570.34 ¹H NMR,400 Hz, (CDCl₃) δ 8.09 (d, foam min 1 H, J = 4.0 Hz), 8.02 (d, 2 H, J =8.0 Hz), Method A 7.64 (d, 2 H, J = 8.0 Hz), 7.41-7.36 (m, 5 H), 6.72(d, 1 H, J = 12.0 Hz), 6.49 (t, 1 H, J = 8.0 Hz), 6.35 (s, br, 1 H),5.87 (s, br, 1 H), 4.80 (d, 1 H, J_(ab) = 16 Hz), 4.30 (d, 1 H, J_(ab) =16 Hz), 3.84 (m, 4 H), 3.55 (s, 2 H), 3.46 (m, 1 H), 2.57 (m, 4 H), 1.89(m, 1 H), 1.60 (m, 2 H), 0.98 (d, 3 H, J = 7.0 Hz), 0.95 (d, 2 H, J =7.0 Hz) 149 8 white 542.15 1.45 542.24 ¹H NMR, 400 Hz, (CDCl₃) δ 7.70(d, solid min 2 H, J = 8.0 Hz), 7.68 (d, 2 H, J = 8.0 Hz), Method A 7.47(d, 2 H, J = 8.0 Hz), 7.38 (d, 2 H, J = 8.0 Hz), 7.29-7.16 (m, 5 H),6.28 (s, br, 1 H), 5.38 (s, br, 1 H), 4.52 (d, 1 H, J_(ab) = 16 Hz),4.42 (d, 1 H, J_(ab) = 16 Hz), 3.54 (s, 2 H), 3.45 (m, 1 H), 2.62 (q, 2H, J = 7.0 Hz), 1.89 (m, 1 H), 1.60 (m, 2 H), 1.08 (t, 3 H, J = 7.0 Hz),0.98 (d, 3 H, J = 7.0 Hz), 0.95 (d, 3 H, J = 7.0 Hz) 150 8 amber 528.121.45 528.33 ¹H NMR, 400 Hz, (CDCl₃) δ 7.72 (d, film min 2 H, J = 8.0Hz), 7.68 (d, 2 H, J = 8.0 Hz), Method A 7.54 (d, 2 H, J = 8.0 Hz), 7.37(d, 2 H, J = 8.0 Hz), 7.35-7.29 (m, 5 H), 6.27 (s, br, 1 H), 5.37 (s,br, 1 H), 4.52 (d, 1 H, J_(ab) = 16 Hz), 4.43 (d, 1 H, J_(ab) = 16 Hz),3.55 (s, 2 H), 3.45 (m, 1 H), 2.17 (s, 3 H), 1.89 (m, 1 H), 1.60 (m, 2H), 0.98 (d, 3 H, J = 7.0 Hz), 0.95 (d, 3 H, J = 7.0 Hz) 151 8 clear542.15 1.46 542.29 ¹H NMR, 400 Hz, (CDCl₃) δ 7.68 (d, glass min 2 H, J =8.0 Hz), 7.64 (d, 2 H, J = 8.0 Hz), Method A 7.45 (d, 2 H, J = 8.0 Hz),7.39-7.26 (m, 4 H), 6.97 (d, 1 H, J = 8.0 Hz), 6.27 (s, br, 1 H), 5.38(s, br, 1 H), 4.54 (d, 1 H, J_(ab) = 16 Hz), 4.44 (d, 1 H, J_(ab) = 16Hz), 3.43 (s, 2 H), 3.25 (t, 1 H, J = 4.0 Hz), 2.77-2.69 (m, 4 H), 2.40(s, 3 H), 1.94 (m, 1 H), 1.60 (m, 2 H), 0.97 (d, 2 H, J = 7.0 Hz), 0.94(d, 2 H, J = 7.0 Hz) 152 8 amber 564.2 1.22 564.32 ¹H NMR, 400 Hz,(CDCl₃) δ 7.69 (d, glass min 2 H, J = 8.0 Hz), 7.59 (d, 2 H, J = 8.0Hz), Method A 7.39-7.33 (m, 4 H), 6.21 (s, br, 1 H), 5.34 (s, br, 1 H),4.76 (d, 1 H, J_(ab) = 16 Hz), 4.31 (d, 1 H, J_(ab) = 16 Hz), 3.57 (s, 2H), 2.69-2.55 (m, 6 H), 2.36-2.18 (m, 12 H), 1.95 (m, 1 H), 1.66-1.50(m, 2 H), 0.98 (d, 3 H, J = 7.0 Hz), 0.94 (d, 3 H, J = 7.0 Hz) 153 5474.21 white 1.78 476.17 ¹H NMR (CDCl₃, 400 MHz) δ 8.41 solid min (br s,2 H), 7.85 (dd, 2 H, J = 2.0, 6.8), Method C 7.46 (dd, 2 H, J = 2.0,6.8), 5.46 (s, 1 H), 4.21 (dd, 1 H, J = 5.9, 8.8), 3.92 (d, 1 H, J =17), 3.77 (d, 1 H, J = 17), 3.27-3.41 (m, 2 H), 2.48-2.62 (m, 6 H),1.80-1.90 (m, 1 H), 1.50-1.72 (m, 3 H), 1.35-1.49 (m, 1 H), 1.05 (t, 6H, J = 7.1), 0.87 (d, 3 H, J = 6.4), 0.85 (d, 3 H, J = 6.7). 154 5 white516.18 1.53 517.30 ¹H NMR (CDCl₃, 500 MHz) δ 7.83 solid min (dd, 2 H, J= 1.9, 6.8), 7.47 (dd, 2 H, J = Method A 2.0, 6.8), 7.31 (br s, 1 H),7.11 (br s, 1 H), 5.57 (br s, 1 H), 4.23 (dd, 1 H, J = 6.8, 8.4),4.00-4.15 (m, 2 H), 3.95 (d, 1 H, J = 17), 3.83 (d, 1 H, J = 17), 2.93(br s, 2 H), 1.75-1.95 (m, 4 H), 1.60-1.75 (1 H, 1.25-1.55 (m, 1 H),1.25 (t, 5 H, J = 7.7), 0.85 (d, 3 H, J = 6.3), 0.83 (d, 3 H, J = 6.3).155 1-Method A white 495.04 1.88 495.1 ¹H NMR (CDCl₃) δ 7.62-7.59 (m,solid min 2 H), 7.43-7.39 (m, 2 H), 7.28-7.25 Method A (m, 2 H),7.22-7.19 (m, 2 H), 6.22 (bs, 1 H), 5.29 (bs, 1 H), 4.53-4.43 (m, 2 H),4.42-4.37 (m, 1 H), 4.16-4.07 (m, 2 H), 1.82-1.73 (m, 1 H), 1.48 (d, 3H, J = 7.3 Hz, isomer A), 1.47 (d, 3 H, J = 7.3 Hz, isomer B), 1.36-1.22(m, 2 H), 1.21 (t, 3 H, J = 7.1 Hz), 0.77 (d, 3 H, J = 6.4 Hz, isomerA), 0.77 (d, 3 H, J = 6.4 Hz, isomer B), 0.65 (d, 3 H, J = 6.7 Hz,isomer A), 0.65 (d, 3 H, J = 6.7 Hz, isomer B). 156 1-Method A white434.07 1.57 (M + H)⁺ ¹H NMR (400 MHz, DMSO) δ 7.80 solid min 435.1 (d, 2H, J = 8.7), 7.66 (d, 2 H, J = 8.3), Method B 7.60 (m, 4 H), 7.53 (s, 1H), 7.10 (s, 1 H), 4.80 (ABq, 2 H, Δυ = 39.8, J_(ab) = 17.2), 4.30 (t, 1H, J = 7.5), 1.60 (m, 1 H), 1.39 (m, 1 H), 0.71 (t, 3 H, J = 7.3). 1571-Method A white 391.08 1.32 (M + H)⁺ ¹H NMR (400 MHz, DMSO) δ 7.81solid min 392.1 (d, 2 H, J = 8.7), 7.78 (d, 2 H, J = 8.4), Method B 7.62(d, 2 H, J = 8.7), 7.57 (d, 2 H, J = 8.3, ), 7.52 (s, 1 H), 7.09 (s, 1H), 4.80 (ABq, 2 H, Δυ = 45.0, J_(ab) = 17.6), 4.28 (t, 1 H, J = 7.5, ),1.58 (m, 1 H), 1.36 (m, 1 H), 0.70 (t, 3 H, J = 7.3). 158 6 white 478.011.53 478.17 ¹H NMR (CD₃OD, 300 MHz) δ 7.80 solid min (ddd, 2 H, J = 1.9,2.4, 8.7), 7.73 (d, Method A 2 H, J = 8.3), 7.48-7.54 (m, 4 H), 4.87 (m,1 H), 4.79 (d, 1 H, J = 16.0), 4.49 (t, 1 H, J = 6.2), 2.81-2.87 (m, 1H), 1.25-1.43 (m, 3 H), 0.83 (d, 3 H, J = 6.2), 0.77-0.83 (m, 2 H),0.63-0.66 (m, 2 H), 0.57 (d, 3 H, J = 6.1). 159 6 white 496.03 1.50496.21 ¹H NMR (CDCl₃, 300 MHz) δ 7.70 solid min (d, 2 H, J = 8.0), 7.68(d, 2 H, J = 8.6), Method A 7.46 (d, 2 H, J = 8.6), 7.41 (d, 2 H, J =8.1), 4.64 (d, 1 H, J = 15.9), 4.43 (d, 1 H, J = 15.9), 4.30 (t, 1 H, J= 6.8), 3.63-3.66 (m, 2 H), 3.55-3.58 (m, 2 H), 3.39 (s, 3 H), 1.76-1.84(m, 1 H), 1.28-1.34 (m, 1 H), 1.05-1.11 (m, 1 H), 0.75 (d, 3 H, J =6.5), 0.66 (d, 3 H, J = 6.7). 160 6 white 551.15 1.33 551.28 ¹H NMR(CDCl₃, 500 MHz) δ 7.72 solid min (d, 2 H, J = 8.2), 7.67 (dd, 2 H, J =Method A 2.0, 8.7), 7.44 (dd, 2 H, J = 1.8, 8.6), 7.39 (d, 2 H, J =8.2), 6.35 (br s, 1 H), 5.46 (br s, 1 H), 4.60 (d, 1 H, J = 15.9), 4.50(d, 1 H, J = 15.9), 4.31 (t, 1 H, J = 7.3), 3.54-3.57 (m, 2 H),2.56-2.64 (m, 6 H), 1.72-1.80 (m, 3 H), 1.28-1.34 (m, 1 H), 1.13-1.16(m, 1 H), 1.03 (t, 6 H, J = 7.2), 0.74 (d, 3 H, J = 6.6), 0.61 (d, 3 H,J = 6.6). 161 9 white 494.06 1.51 494.2 ¹H NMR (CDCl₃) δ 7.69 (d, 2 H,solid min J = 7.0 Hz), 7.45-7.47 (m, 4 H), 7.30 (d, Method B 2 H, J =8.0 Hz), 7.12 (s, br, 1 H), 6.25 (s, br, 1 H), 5.22 (s, br, 1 H), 4.40(dd, 2 H, J = 50 Hz, 15 Hz), 4.25 (t, 1 H, J = 7.4 Hz), 2.48-2.51 (m, 1H), 1.54- 1.86 (m, 1 H), 1.17-1.34 (m, 10 H), 0.75 (d, 3 H, J = 7.0 Hz),0.67 (d, 3 H, J = 7.0 Hz). 162 9 tan 504.01 1.52 504.1 ¹H NMR (CDCl₃) δ8.10 (s, br, 1 H), solid min 7.67 (d, 2 H, J = 7.0 Hz), 7.58 (d, 2 H,Method B J = 7.0 Hz), 7.23-7.49 (m, 6 H), 6.54- 6.57 (m, 1 H), 6.27 (s,br, 1 H), 5.50 (s, br, 1 H), 4.51 (dd, 2 H, J = 50 Hz, 15 Hz), 4.28 (t,1 H, J = 7.4 Hz), 1.78- 1.85 (m, 1 H), 1.12-1.32 (m, 2 H), 0.75 (d, 3 H,J = 7.0 Hz), 0.67 (d, 3 H, J = 7.0 Hz). 163 9 white 451.98 1.50 450.18¹H NMR (CDCl₃) δ 7.67 (d, 2 H, solid min (M − H⁻) J = 8.0 Hz), 7.28-7.46(m, 6 H), 7.12 (s, Method B br, 1 H), 6.24 (s, br, 1 H), 5.19 (s, br, 1H), 4.48 (dd, 2 H, J = 50 Hz, 15 Hz), 4.27 (t, 1 H, J = 7.0 Hz), 2.18(s, 3 H), 1.80-2.01 (m, 1 H), 1.12-1.32 (m, 2 H), 0.75 (d, 3 H, J = 7.0Hz), 0.67 (d, 3 H, J = 7.0 Hz). 164 8 white 491.06 1.31 491.24 ¹H NMR,400 Hz, (CDCl₃) δ 7.69 (d, solid min 2 H, J = 8.0 Hz), 7.64 (d, 2 H, J =8.0 Hz), Method A 7.51 (d, 2 H, J = 8.0 Hz), 7.37 (d, 2 H, J = 8.0 Hz),6.25 (s, br, 1 H), 5.35 (s, br, 1 H), 4.59 (d, 1 H, J_(ab) = 16 Hz),4.36 (d, 1 H, J_(ab) = 16 Hz), 3.62 (s, 2 H), 3.25 (t, 1 H, J = 6.0 Hz),2.55-2.48 (m, 7 H), 1.94 (m, 1 H), 1.60 (m, 2 H), 0.97 (d, 3 H, J = 7.0Hz), 0.94 (d, 3 H, J = 7.0 Hz) 165 8 white 520.14 1.40 520.32 ¹H NMR,400 Hz, (CDCl₃) δ 7.72 (d, solid min 2 H, J = 8.0 Hz), 7.66 (d, 2 H, J =8.0 Hz), Method A 7.51 (d, 2 H, J = 8.0 Hz), 7.37 (d, 2 H, J = 8.0 Hz),6.28 (s, br, 1 H), 5.39 (s, br, 1 H), 4.52 (d, 1 H, J_(ab) = 16 Hz),4.43 (d, 1 H, J_(ab) = 16 Hz), 3.57 (s, 2 H), 3.25 (t, 1 H, J = 6.0 Hz),2.59 (t, 2 H, J = 8.0 Hz), 2.30 (d, 2 H, J = 6.0 Hz), 2.01-1.90 (m, 1H), 1.68-1.49 (m, 4 H), 1.02 (m, 1 H), 0.98 (d, 3 H, J = 7.0 Hz), 0.94(d, 3 H, J = 7.0 Hz), 0.89 (t, 3 H, J = 8.0 Hz), 0.44-0.31 (m, 4 H) 1668 clear 506.11 1.41 506.31 ¹H NMR, 400 Hz, (CDCl₃) δ 7.73 (d, glass min2 H, J = 8.0 Hz), 7.65 (d, 2 H, J = 8.0 Hz), Method A 7.44 (d, 2 H, J =8.0 Hz), 7.38 (d, 2 H, J = 8.0 Hz), 6.27 (s, br, 1 H), 5.39 (s, br, 1H), 4.56 (d, 1 H, J_(ab) = 16 Hz), 4.42 (d, 1 H, J_(ab) = 16 Hz), 3.45(d, 1 H, J_(ab) = 12 Hz), 3.28 (d, 1 H, J_(ab) = 12 Hz), 3.25 (t, 1 H, J= 6.0 Hz), 2.75 (m, 4 H), 2.0-1.53 (m, 7 H), 1.35 (m, 1 H), 1.17 (m, 1H), 0.97 (d, 3 H, J = 7.0 Hz), 0.94 (d, 3 H, J = 7.0 Hz), 0.87 (m, 3 H)167 8 clear 506.11 1.42 506.30 ¹H NMR, 400 Hz, (CDCl₃) δ 7.71 (d, glassmin 2 H, J = 8.0 Hz), 7.65 (d, 2 H, J = 8.0 Hz), Method A 7.43 (d, 2 H,J = 8.0 Hz), 7.37 (d, 2 H, J = 8.0 Hz), 6.26 (s, br, 1 H), 5.40 (s, br,1 H), 4.56 (d, 1 H, J_(ab) = 16 Hz), 4.42 (d, 1 H, J_(ab) = 16 Hz), 3.48(s, 2 H), 3.25 (t, 1 H, J = 6.0 Hz), 2.56-2.42 (m, 4 H), 1.93 (m, 1 H),1.89-1.48 (m, 6 H), 1.34 (m, 1 H), 0.98-0.93 (m, 9 H) 168 8 clear 546.181.46 546.35 ¹H NMR, 400 Hz, (CDCl₃) δ 7.72 (d, glass min 2 H, J = 8.0Hz), 7.65 (d, 2 H, J = 8.0 Hz), Method A 7.42 (d, 2 H, J = 8.0 Hz), 7.38(d, 2 H, J = 8.0 Hz), 6.27 (s, br, 1 H), 5.40 (s, br, 1 H), 4.52 (d, 1H, J_(ab) = 16 Hz), 4.43 (d, 1 H, J_(ab) = 16 Hz), 3.45 (d, 1 H, J_(ab)= 12 Hz), 3.28 (d, 1 H, J_(ab) = 12 Hz), 3, 25 (t, 1 H, J = 6.0 Hz),2.87 (m, 1 H), 2.70-2.56 (m, 3 H), 2.39 (m, 1 H), 2.31-2.19 (m, 4 H),1.95 (m, 1 H), 1.77 (m, 1 H), 1.68-1.59 (m, 2 H), 1.54-1.44 (m, 4 H),1.28 (m, 2 H), 0.98 (d, 3 H, J = 7.0 Hz), 0.94 (d, 2 H, J = 7.0 Hz) 1698 clear 508.13 1.39 502.28 ¹H NMR, 400 Hz, (CDCl₃) δ 7.70 (d, glass min2 H, J = 8.0 Hz), 7.68 (d, 2 H, J = 8.0 Hz), Method A 7.55 (d, 2 H, J =8.0 Hz), 7.38 (d, 2 H, J = 8.0 Hz), 6.28 (s, br, 1 H), 5.37 (s, br, 1H), 4.57 (d, 1 H, J_(ab) = 16 Hz), 4.36 (d, 1 H, J_(ab) = 16 Hz), 3.38(s, 2 H), 3.25 (t, 1 H, J = 6.0 Hz), 2.83 (m, 2 H), 1.92 (m, 1 H), 1.60(m, 2 H), 0.98 (d, 3 H, J = 7.0 Hz), 0.94 (d, 3 H, J = 7.0 Hz), 0.84 (s,6 H), 0.82 (s, 6 H) 170 8 clear 494.1 1.34 494.26 ¹H NMR, 400 Hz,(CDCl₃) δ 7.69 (d, glass min 2 H, J = 8.0 Hz), 7.67 (d, 2 H, J = 8.0Hz), Method A 7.44 (d, 2 H, J = 8.0 Hz), 7.38 (d, 2 H, J = 8.0 Hz), 6.27(s, br, 1 H), 5.39 (s, br, 1 H), 4.52 (d, 1 H, J_(ab) = 16 Hz), 4.44 (d,1 H, J_(ab) = 16 Hz), 3.40 (s, 2 H), 3.25 (t, 1 H, J = 6.0 Hz), 2.39 (s,3 H), 1.94 (m, 1 H), 1.68-1.50 (m, 2 H), 1.43 (m, 2 H), 1.30 (m, 2 H),0.98 (d, 3 H, J = 7.0 Hz), 0.94 (d, 3 H, J = 7.0 Hz), 0.86 (t, 3 H, J =7.0 Hz) 171 8 clear 508.13 1.40 508.27 ¹H NMR, 400 Hz, (CDCl₃) δ 7.69(d, glass min 2 H, J = 8.0 Hz), 7.64 (d, 2 H, J = 8.0 Hz), Method A7.4-7.33 (m, 4 H), 6.25 (s, br, 1 H), 5.35 (s, br, 1 H), 4.52 (d, 1 H,J_(ab) = 16 Hz), 4.43 (d, 1 H, J_(ab) = 16 Hz), 3.46 (s, 2 H), 3.25 (t,1 H, J = 6.0 Hz), 2.62 (t, 2 H, J = 6.0 Hz), 2.52 (q, 2 H, J = 7.0 Hz),1.94 (m, 1 H), 1.68-1.45 (m, 4 H), 1.29 (m, 2 H), 1.02 (t, 3 H, J = 7.0Hz), 0.98 (d, 3 H, J = 7.0 Hz), 0.94 (d, 3 H, J = 7.0 Hz), 0.88 (t, 3 H,J = 7.0 Hz) 172 8 amber 575.22 1.34 575.32 ¹H NMR, 400 Hz, (CDCl₃) δ7.72 (d, glass min 2 H, J = 8.0 Hz), 7.59 (d, 2 H, J = 8.0 Hz), Method A7.39-7.33 (m, 4 H), 6.25 (s, br, 1 H), 5.36 (s, br, 1 H), 4.53 (d, 1 H,J_(ab) = 16 Hz), 4.39 (d, 1 H, J_(ab) = 16 Hz), 3.57 (s, 2 H), 3.25 (t,1 H, J = 6.0 Hz), 2.62-2.32 (m, 9 H), 1.94 (m, 1 H), 1.68-1.50 (m, 2 H),1.48-1.20 (m, 12 H), 0.98 (d, 3 H, J = 7.0 Hz), 0.94 (d, 3 H, J = 7.0Hz) 173 6 white 436.92 1.52 437.16 ¹H NMR (dmso-d₆, 300 MHz) δ 7.85solid min (d, 2 H, J = 8.4), 7.82 (dd, 2 H, J = Method A 1.8, 8.7), 7.61(dd, 2 H, J = 1.8, 8.7), 7.54 (br s, 1 H), 7.47 (d, 2 H, J = 8.4), 7.09(br s, 1 H), 4.85 (d, 1 H, J = 17.4), 4.69 (d, 1 H, J = 17.1), 4.42 (t,1 H, J = 7.2), 1.40-1.48 (m, 1 H), 1.27-1.34 (m, 1 H), 0.42-0.47 (m, 1H), 0.25-0.30 (m, 2 H), 0.00-0.03 (m, 1 H), −0.10-−0.07 (m, 1 H). 1741-Method A off-white 492.11 2.13 M + Na ¹H NMR (DMSO) δ 7.76 (d, 2 H,solid min 514.95 J = 6.8 Hz), 7.61 (m, 6 H), 7.44 (s, br, Method D 1 H),7.13 (s, br, 1 H), 4.78 (dd, 2 H, J = 52 Hz, 16 Hz), 4.58 (t, 1 H, J =8.0 Hz), 3.47 (d, 2 H, J = 6.0 Hz), 0.88 (s, 9 H) 175 1-Method A white449.12 1.94 M + Na ¹H NMR (DMSO) δ 7.77 (m, 4 H), solid min 471.97 7.60(m, 4 H), 7.45 (s, br, 1 H), 7.12 Method D (s, br, 1 H), 4.78 (dd, 2 H,J = 56 Hz, 20 Hz), 4.57 (t, 1 H, J = 8.0 Hz), 3.47 (d, 2 H, J = 6.0 Hz),0.88 (s, 9 H) 176 1-solid 478.90 1.86 479.02 support Method B 1771-solid 426.90 1.82 449.02 support Method B M + Na 178 1-solid 496.001.81 496.06 support Method B 179 1-solid 412.90 1.72 413.04 supportMethod B 180 1-solid 423.00 1.86 445.02 support Method B M + Na 1811-solid 501.10 1.94 523.04 support Method B M + Na 182 1-solid 413.901.53 414.05 support Method B 183 1-solid 423.00 1.88 423.08 supportMethod B 184 1-solid 467.00 1.60 467.06 support Method B 185 1-solid505.00 1.89 505.07 support Method B 186 1-solid 478.90 1.84 479.02support Method B 187 1-solid 505.00 1.93 505.06 support Method B 1881-solid 429.40 1.80 450.90 support Method B M + Na 189 1-solid 423.001.89 423.09 support Method B 190 1-solid 425.00 1.92 425.11 supportMethod B 191 1-solid 487.00 1.91 487.04 support Method B 192 1-solid437.00 1.95 459.05 support Method B M + Na 193 1-solid 358.90 1.67381.07 support Method B M + Na 194 1-solid 473.80 1.86 472.9 supportMethod B 195 1-solid 430.9 1.75 431.04 support Method B 196 1-solid379.30 1.65 400.98 support Method B 197 1-solid 421.00 1.82 443.06support Method B M + Na 198 1-solid 379.30 1.64 400.99 support Method B199 1-solid 495.00 1.95 494.98 support Method B 200 1-solid 465.10 2.05487.10 support Method B M + Na 201 1-solid 483.00 1.72 483.04 supportMethod B 202 1-solid 463.80 1.91 486.96 support Method B M + Na 2031-solid 430.90 1.77 431.04 support Method B 204 1-solid 409.00 1.79409.07 support Method B 205 1-solid 462.90 1.81 463.04 support Method B206 1-solid 423.00 1.86 423.10 support Method B 207 1-solid 491.80 1.88492.91 support Method B 208 1-solid 409.00 1.78 431.04 support Method BM + Na 209 1-solid 419.9 1.58 442.04 support Method B M + Na 210 1-solid344.90 1.56 367.05 support Method B M + Na 211 1-solid 480.90 1.87481.02 support Method B 212 1-solid 430.90 1.76 453.02 support Method B213 1-solid 455.00 1.71 455.07 support Method B 214 1-solid 515.00 1.91515.09 support Method B 215 1-solid 447.40 1.82 468.99 support Method BM + Na 216 1-solid 480.90 1.80 481.00 support Method B 217 1-solid402.90  1.600 403.12 support Method B 218 1-solid 429.40 1.78 429.04support Method B 219 1-solid 448.90 1.78 471.00 support Method B 2201-solid 430.90 1.75 453.03 support Method B 221 1-solid 480.90 1.85503.00 support Method B M + Na 222 1-solid 445.00 1.87 467.06 supportMethod B M + Na 223 1-solid 453.00 1.62 453.03 support Method B 2241-solid 453.00 1.63 453.05 support Method B 225 1-solid 416.00 1.53416.04 support Method B 226 1-solid 401.90 1.45 401.96 support Method B227 1-solid 395.90 1.12 396.01 support Method B 228 1-solid 358.90 1.62381.01 support Method B M + Na 229 1-solid 439.00 1.80 460.97 supportMethod B M + Na 230 1-solid 424.90 1.72 425.03 support Method B 2311-solid 463.80 1.85 464.90 support Method B 232 1-solid 456.90 1.64456.02 support Method B 233 1-solid 447.40 1.78 468.92 support Method BM + Na 234 1-Method A white 419.11 1.91 (M + Na)⁺ ¹H NMR (400 MHz, DMSO)δ 7.82 solid min 442.0 (d, 2 H, J = 8.7), 7.80 (d, 2 H, J = 8.4), MethodF 7.62 (d, 2 H, J = 8.7), 7.59 (d, 2 H, J = 8.3, ), 7.51 (s, 1 H), 7.07(s, 1 H), 4.81 (ABq, 2 H, Δυ = 38.0, J_(ab) = 17.5), 4.31 (t, 1 H, J =6.7), 1.54 (m, 1 H), 1.29 (m, 1 H), 1.03 (m, 3 H), 0.85 (m, 1 H), 0.66(t, 3 H, J = 6.9). 235 1-Method A white 462.10 2.13 (M + Na)⁺ ¹H NMR(400 MHz, DMSO) δ 7.81 solid min 485.0 (d, 2 H, J = 8.7), 7.69 (d, 2 H,J = 8.3), Method F 7.61 (m, 4 H), 7.51 (s, 1 H), 7.07 (s, 1 H), 4.82(ABq, 2 H, Δυ = 31.9, J_(ab) = 17.1), 4.32 (t, 1 H, 8.3), 1.53 (m, 1 H),1.31 (m, 1 H), 1.05 (m, 3 H), 0.88 (m, 1 H), 0.63 (t, 3 H, J = 6.8). 2361-solid white 530.92 1.92 530.99 support solid Method B 237 1-solidwhite 416.93 1.61 417.07 support solid Method B 238 1-solid white 466.991.62 467.06 support solid Method B 239 1-solid white 379.13 1.62 400.98support solid M + Na 240 1-solid white 395.91 1.13 396.01 support solid241 8 amber 592.29 1.69 592.39 ¹H NMR, 400 Hz, (CDCl₃) δ 7.72 (d, glassmin 2 H, J = 8.0 Hz), 7.65 (d, 2 H, J = 8.0 Hz), Method A 7.43 (d, 2 H,J = 8.0 Hz), 7.37 (d, 2 H, J = 8.0 Hz), 6.27 (s, br, 1 H), 5.40 (s, br,1 H), 4.56 (d, 1 H, J_(ab) = 16 Hz), 4.40 (d, 1 H, J_(ab) = 16 Hz), 3.56(s, 2 H), 3.25 (t, 1 H, J = 6.0 Hz), 2.40 (t, 4 H, J = 6.0 Hz), 1.95 (m,1 H), 1.68-1.52 (m, 2 H), 1.42 (q, 4 H, J = 6.0 Hz), 1.28- 1.22 (m, 12H), 0.98 (d, 3 H, J = 7.0 Hz), 0.88 (t, 6 H, J = 6.0 Hz) 242 8 amber648.4 1.88 648.43 ¹H NMR, 400 Hz, (CDCl₃) δ 7.71 (d, glass min 2 H, J =8.0 Hz), 7.64 (d, 2 H, J = 8.0 Hz), Method A 7.43 (d, 2 H, J = 8.0 Hz),7.37 (d, 2 H, J = 8.0 Hz), 6.27 (s br, 1 H), 5.40 (s, br, 1 H), 4.56 (d,1 H, J_(ab) = 16 Hz), 4.40 (d, 1 H, J_(ab) = 16 Hz), 3.56 (s, 2 H), 3.25(t, 1 H, J = 6.0 Hz), 2.47 (t, 4 H, J = 6.0 Hz), 1.95 (m, 1 H),1.68-1.50 (m, 2 H), 1.43-1.14 (m, 14 H), 0.98 (d, 3 H, J = 7.0 Hz), 0.94(d, 3 H, J = 7.0 Hz), 0.88 (t, 6 H, J = 6.0 Hz) 243 9 clear 524.08 1.35542.25 ¹H NMR, 400 Hz, (CDCl₃) δ 7.69 (d, glass min 2 H, J = 8.0 Hz),7.64 (d, 2 H, J = 8.0 Hz), Method A 7.50 (d, 2 H, J = 8.0 Hz), 7.38 (d,2 H, J = 8.0 Hz), 6.25 (s, br, 1 H), 5.34 (s, br, 1 H), 4.70 (d, 1 H,J_(ab) = 16 Hz), 4.48 (d, 1 H, J_(ab) = 16 Hz), 4.24-4.08 (m, 4 H), 3.42(s, 2 H), 3.25 (t, 1 H, J = 6 Hz), 2.51 (s, 3 H), 1.94 (M, 1 H),1.68-1.54 (m, 2 H), 1.22 (t, 3 H, J = 6.0 Hz), 0.98 (d, 3 H, J = 7.0Hz), 0.94 (d, 3 H, J = 7.0 Hz) 244 6 white 565.14 1.29 564.99 ¹H NMR(CDCl₃, 300 MHz) δ 8.12 solid min (br s, 1 H), 7.77 (d, 2 H, J = 8.8),7.70 Method B (d, 2 H, J = 8.6), 7.47 (d, 2 H, J = 8.4), 7.45 (d, 2 H, J= 8.0), 6.25 (br s, 1 H), 5.31 (br s, 1 H), 4.66 (d, 1 H, J = 15.7),4.38 (d, 1 H, J = 15.8), 4.27 (t, 1 H, J = 7.1), 3.51-3.89 (m, 4 H),2.35-2.74 (m, 4 H), 1.78-1.88 (m, 2 H), 1.40-1.65 (m, 4 H), 1.24-1.32(m, 2 H), 1.03-1.10 (m, 1 H), 0.74 (d, 3 H, J = 6.5), 0.65 (d, 3 H, J =6.6). 245 6 white 437.95 1.36 438.20 ¹H NMR (CDCl₃, 300 MHz) δ 7.72solid min (dd, 2 H, J = 8.3), 7.69 (dd, 2 H, J = Method B 1.9, 8.7),7.46 (dd, 2 H, J = 1.8, 8.7), 7.44 (d, 2 H, J = 8.6), 6.21 (br s, 1 H),5.98 (br s, 1 H), 5.88 (br s, 1 H), 5.39 (br s, 1 H), 4.66 (d, 1 H, J =15.7), 4.41 (d, 1 H, J = 15.9), 4.29 (t, 1 H, J = 6.5), 1.77-1.87 (m, 1H), 1.25-1.36 (m, 1 H), 1.03-1.11 (m, 1 H), 0.75 (d, 3 H, J = 6.6), 0.65(d, 3 H, J = 6.6). 246 6 white 549.14 1.34 549.00 ¹H NMR (CDCl₃, 300MHz) δ 7.82 solid min (d, 2 H, J = 7.8), 7.67 (dd, 2 H, J = Method B2.0, 8.7), 7.40-7.46 (m, 5 H), 6.22 (br s, 1 H), 5.23 (br s, 1 H), 4.61(d, 1 H, J = 15.9), 4.42 (d, 1 H, J = 15.7), 4.28 (t, 1 H, J = 7.2),3.60-3.69 (m, 2 H), 2.45-2.83 (m, 6 H), 1.40-1.85 (m, 7 H), 1.24-1.35(m, 1 H), 1.05-1.14 (m, 1 H), 0.75 (d, 3 H, J = 6.5), 0.66 (d, 3 H, J =6.6). 247 6 white 524.11 1.61 523.94 ¹H NMR (CDCl₃, 300 MHz) δ 7.68solid min (d, 2 H, J = 8.4), 7.46 (d, 2 H, J = 8.4), Method B 7.39 (d, 2H, J = 8.1), 7.29 (d, 2 H, J = 8.1), 6.20 (br s, 1 H), 5.24 (br s, 1 H),4.60 (d, 1 H, J = 15.8), 4.44 (d, 1 H, J = 15.9), 4.30 (t, 1 H, J =6.9), 3.70- 4.05 (br m, 4 H), 2.45-2.60 (m, 4 H), 1.73-1.80 (m, 1 H),1.28-1.35 (m, 1 H), 1.05-1.14 (m, 1 H), 0.76 (d, 3 H, J = 6.5), 0.66 (d,3 H, J = 6.6). 248 2 red 466.00 1.48 466.2 ¹H NMR (CDCl₃) δ 7.65 (d, 2H, solid min J = 7.0 Hz), 7.41 (d, 2 H, J = 7.0 Hz), Method B 7.20 (d, 2H, J = 8.8 Hz), 6.79 (d, 2 H, J = 8.8 Hz), 6.23 (s, br, 1 H), 5.20 (s,br, 1 H), 4.32 (dd, 2 H, J = 50 Hz, 15 Hz), 4.19-4.27 (m, 1 H),3.84-3.87 (m, 4 H), 3.12-3.16 (m, 4 H), 1.91- 1.95 (m, 1 H), 1.35-1.39(m, 1 H), 0.92-1.06 (m, 2 H), 0.74 (t, 3 H, J = 8.0 Hz). 249 2 yellow479.05 1.18 479.02 ¹H NMR (CDCl₃) δ 7.63 (d, 2 H, solid min J = 8.0 Hz),7.40 (d, 2 H, J = 8.0 Hz), Method B 7.19 (d, 2 H, J = 8.8 Hz), 6.78 (d,2 H, J = 8.8 Hz), 6.25 (s, br, 1 H), 5.21 (s, br, 1 H), 4.36 (dd, 2 H, J= 50 Hz, 15 Hz), 4.20-4.27 (m, 1 H), 3.28-3.35 (m, 4 H), 2.69-2.76 (m, 4H), 2.48 (s, 3 H), 1.93-1.97 (m, 1 H), 1.35-1.39 (m, 1 H), 0.90-1.07 (m,2 H), 0.72 (t, 3 H, J = 8.0 Hz). 250 2 tan 474.03 1.92 474.2 ¹H NMR(CDCl₃) δ 7.68 (d, 2 H, solid min J = 8.8 Hz), 7.43-7.45 (m, 4 H), 7.12(d, Method B 2 H, J = 8.8 Hz), 6.78 (d, 2 H, J = 8.8 Hz), 6.19 (s, br, 1H), 5.18 (s, br, 1 H), 4.56 (dd, 2 H, J = 50 Hz, 15 Hz), 4.21-4.30 (m, 1H), 2.01 (s, 6 H), 1.93-1.97 (m, 1 H), 1.35-1.39 (m, 1 H), 0.90-1.07 (m,2 H), 0.72 (t, 3 H, J = 8.0 Hz). 251 6 white 482.00 2.01 479.07 ¹H NMR(CDCl₃, 300 MHz) δ 7.67 solid min (ddd, 2 H, J = 1.9, 2.4, 8.7), 7.58(d, Method B 2 H, J = 8.1), 7.43 (ddd, 2 H, J = 1.5, 2.4, 8.7), 7.37 (d,2 H, J = 8.2), 6.30 (br s, 1 H), 5.70 (br s, 1 H), 4.62 (d, 1 H, J =15.9), 4.46 (d, 1 H, J = 15.9), 4.32 (t, 1 H, J = 7.3), 3.51 (s, 3 H),3.32 (s, 3 H), 1.73-1.80 (m, 1 H), 1.28-1.35 (m, 1 H), 1.05-1.14 (m, 1H), 0.74 (d, 3 H, J = 6.5), 0.61 (d, 3 H, J = 6.6). 252 1-Method A white466.98 1.92 467.2 ¹H NMR (CDCl₃) δ 7.92 (d, 1 H, solid min J = 8.0 Hz),7.79 (A of ABq, 2 H, Method A J = 8.8 Hz), 7.72 (d, 1 H, J = 7.7 Hz),7.50 (B of ABq, 2 H, J = 8.8 Hz), 7.31 (t, 1 H, J = 7.7 Hz), 6.29 (bs, 1H), 5.21 (bs, 1 H), 5.02 (s, 2 H), 4.35 (q, 2 H, J = 7.0 Hz), 4.27 (dd,1 H, J = 8.6, 5.5 Hz), 1.88-1.78 (m, 1 H), 1.39 (t, 3 H, J = 7.0 Hz),1.37-1.29 (m, 1 H), 1.02-0.93 (m, 1 H), 0.75 (d, 3 H, J = 6.6 Hz), 0.66(d, 3 H, J = 6.6 Hz). 253 1-Method A white 481.01 1.81 481.2 ¹H NMR(CDCl₃) δ 7.67 (A of ABq, solid min 2 H, J = 8.8 Hz), 7.44 (B of ABq, 2H, Method A J = 8.8 Hz), 7.27-7.15 (m, 3 H), 6.24 (bs, 1 H), 5.26 (bs, 1H), 4.55 (A of ABq, 1 H, J = 15.4 Hz), 4.39 (B of ABq, 1 H, J = 15.4Hz), 4.29 (t, 1 H, J = 7.0 Hz), 4.15 (q, 2 H, J = 7.2 Hz), 1.87-1.78 (m,1 H), 1.37- 1.29 (m, 1 H), 1.26 (t, 3 H, = 7.2 Hz), 1.24-1.13 (m, 1 H),0.76 (d, 3 H, J = 6.2 Hz), 0.67 (d, 3 H, J = 6.6 Hz). 254 10 white438.98 1.20 439.05 ¹H NMR (CDCl₃) TFA salt: δ 8.04 solid Method B (s, 1H), 8.03 (d, 1 H, J = 9.80 Hz), 7.76 (d, 2 H, J = 7.6 Hz), 7.54 (d, 2 H,J = 7.6 Hz), 6.83 (d, 1 H, J = 9.8 Hz), 6.62 (br s, 1 H), 6.40 (br s, 1H), 4.64 (d, 1 H, J = 15.9 Hz), 4.29 (m, 1 H), 4.18 (d, 1 H, J = 15.9Hz), 3.30 (s, 6 H), 1.84 (m, 1 H), 1.29 (m, 1 H), 0.93 (m, 1 H), 0.77(d, 3 H, J = 6.5 Hz), 0.72 (d, 3 H, J = 6.5 Hz) 255 1-Method A light450.14 2.02 450.98 ¹H NMR (DMSO) δ 7.78 (d, 2 H, J = orange min 8.4 Hz),7.58 (d, 2 H, J = 8.8 Hz), 7.47 residue Method E (s, br, 1 H), 7.29 (d,2 H, J = 8.8 Hz), 7.00 (s br, 1 H), 6.87 (d, 2 H, J = 8.8 Hz), 6.03 (m,1 H), 5.32 (dd, 2 H, J = 12 Hz, 56 Hz), 4.63 (m, 4 H), 5.32 (dd, 2 H, J= 12 Hz, 56 Hz), 4.35 (m, 1 H), 1.33 (m, 3 H), 0.80 (d, 3 H, J = 6.0Hz), 0.50 (d, 3 H, J = 6.0 Hz), 256 7 white 548.22 1.87 549.00 ¹H NMR(CDCl₃, 300 MHz) δ 7.71 solid min (d, 2 H, J = 8.6), 7.71 (d, 2 H, J =8.9), Method A 7.15-7.35 (m, 5 H), 6.64 (s, 1 H), 5.86 (s, 1 H), 4.15(dd, 1 H, J = 5.2, 9.5), 3.88 (d, 1 H, J = 13), 3.76 (d, 1 H, J = 13),3.46 (t, 2 H, J = 6.7), 3.21-3.29 (m, 1 H), 2.97 (dd, 1 H, J = 4.6, 14),2.65-2.85 (m, 4 H), 1.75-1.95 (m, 3 H), 1.00-1.30 (m, 5 H), 0.75-0.80(m, 1 H), 0.72 (d, 3 H, J = 6.7), 0.67 (d, 3 H, J = 6.7). 257 7 white520.19 1.74 521.31 ¹H NMR (CDCl₃, 500 MHz) δ 7.72 solid min (d, 2 H, J =8.8), 7.51 (d, 2 H, J = 8.8), Method A 7.33 (d, 2 H, J = 7.6), 7.28 (d,2 H, J = 7.6), 7.03 (t, 1 H, J = 7.3), 6.67 (s, 1 H), 5.42 (s, 1 H),3.97-4.22 (m, 3 H), 3.27-3.35 (m, 1 H), 2.78-3.02 (m, 3 H), 1.83-1.99(m, 3 H), 1.09-1.42 (m, 4 H), 0.75-0.82 (m, 1 H), 0.74 (d, 3 H J = 6.4),0.67 (d, 3 H, J = 6.7). 258 7 white 526.24 1.81 527.34 ¹H NMR (CDCl₃,500 MHz) δ 7.73 solid min (d, 2 H, J = 8.9), 7.51 (d, 2 H, 8.9), MethodA 6.65 (s, 1 H), 5.37 (s, 1 H), 4.15 (dd, 1 H, J = 5.1, 6.5), 3.92 (d, 1H, J = 12), 3.82 (d, 1 H, J = 14), 3.57-3.67 (m, 1 H), 3.26 (dd, 1 H, J= 10, 14), 2.98 (dd, 1 H, J = 4.5, 14), 2.74 (q, 2 H, J = 12, 24),1.80-1.97 (m, 5 H), 1.64-1.72 (m, 3 H), 1.00-1.43 (m, 10 H), 0.75-0.82(m, 1 H), 0.73 (d, 3 H, J = 6.4), 0.67 (d, 3 H, 6.7). 259 7 white 548.221.78 549.32 ¹H NMR (CDCl₃, 500 MHz) δ 7.71 solid min (d, 2 H, J = 8.2),7.50 (d, 2 H, J = 8.5), Method A 7.30 (d, 4 H, J = 4.3), 7.20-7.25 (m, 1H), 6.65 (s, 1 H), 5.74 (s, 1 H), 4.99 (t, 1 H, J = 7.02), 4.70-4.77 (m,1 H), 4.10-4.25 (m, 1 H), 4.00 (d, 1 H, J = 13), 3.90 (d, 1 H, J = 13),3.15-3.35 (m, 1 H), 2.90-3.00 (m, 1 H), 2.60- 2.75 (m, 2 H), 1.50-1.95(m, 5 H), 1.46 (d, 3 H, J = 6.7), 1.00-1.30 (m, 2 H), 0.75-0.83 (m, 1H), 0.73 (d, 3 H, J = 6.4), 0.67 (d, 3 H, J = 6.4). 260 7 white 588.181.90 589.25 ¹H NMR (CDCl₃, 500 MHz) δ 7.73 solid min (d, 2 H, J = 8.9),7.62 (d, 4 H, J = 8.6), Method A 7.45 (d, 2 H, J = 8.5), 6.67 (s, 1 H),6.52 (s, 1 H), 4.45 (s, 1 H), 4.16 (dd, 1 H, J = 5.2, 9.8), 4.12 (d, 1H, J = 12), 4.03 (d, 1 H, J = 14), 3.80 (dd, 1 H, J = 10, 14), 3.00 (dd,1 H, J = 4.5, 14), 2.84-2.92 (m, 2 H), 1.85- 2.00 (m, 3 H), 1.69 (d, 1H, J = 12), 1.10-1.35 (m, 3 H), 0.75-0.82 (m, 1 H), 0.74 (d, 3 H, J =6.7), 0.68 (d, 3 H, J = 6.7). 261 7 white 554.14 1.86 555.24 ¹H NMR(CDCl₃, 500 MHz) δ 7.73 solid min (d, 2 H, J = 8.6), 7.52 (d, 2 H, J =8.9), Method A 7.45 (s, 1 H), 7.18 (d, 2 H, J = 6.7), 6.95-7.02 (m, 1H), 6.65 (s, 1 H), 6.50 (s, 1 H), 5.50 (s, 1 H), 4.16 (dd, 1 H, J = 5.2,9.5), 4.08 (d, 1 H, J = 15), 3.99 (d, 1 H, J = 14), 3.30 (dd, 1 H, J =10, 15), 2.99 (dd, 1 H, J = 4.5, 15), 2.80- 2.92 (m, 2 H), 1.80-2.00 (m,3 H), 1.67 (d, 1 H, J = 13), 1.05-1.40 (m, 4 H), 0.75-0.80 (m, 1 H),0.74 (d, 3 H, J = 6.7), 0.68 (d, 3 H, J = 6.7). 262 7 white 592.21 1.86593.30 ¹H NMR (CDCl₃, 500 MHz) δ 7.96 solid min (d, 2 H, J = 8.9), 7.73(d, 2 H, J = 8.9), Method A 7.51 (d, J = 8.6), 7.42 (d, 2 H, J = 8.6),6.65 (s, 2 H), 5.45 (s, 1 H), 4.83 (q, 2 H, J = 7.0), 4.16 (dd, 1 H, J =5.2, 9.8), 4.11 (d, 1 H, J = 13), 4.03 (d, 1 H, J = 13), 3.30 (dd, 1 H,J = 10, 14), 3.00 (dd, 1 H, J = 4.2, 14), 2.81- 2.95 (m, 2 H), 1.84-2.01(m, 3 H), 1.68 (d, 1 H, J = 13), 1.37 (t, 3 H, J = 7.3), 1.08-1.34 (m, 4H), 0.76-0.82 (m, 1 H), 0.74 (d, 3 H, J = 6.7), 0.68 (d, 3 H, J = 6.7).263 7 white 530.20 2.18 531.11 ¹H NMR (CDCl₃, 500 MHz) δ 7.73 solid min(d, 2 H, J = 8.5), 7.51 (d, 2 H, J = 8.6), Method C 6.67 (s, 1 H), 5.41(s, 1 H), 4.97 (s, 1 H), 4.20 (q, 2 H, J = 7.0), 4.15 (dd, 1 H, J = 5.1,9.5), 3.90-4.04 (m, 4 H), 3.26 (dd, 1 H, J = 10, 14), 2.99 (dd, 1 H, J =4.5, 14), 2.70-2.82 (m, 2 H), 1.80-1.95 (m, 3 H), 1.28 (t, 3 H, J =7.3), 1.05-1.25 (m, 3 H), 0.75-0.80 (m, 1 H), 0.72 (d, 3 H, J = 6.7),0.67 (d, 3 H, J = 6.4). 264 1-Method A white 462.96 1.47 462.98 ¹H NMR(CDCl₃) δ 7.81 (d, 2 H, solid min J = 8.4 Hz), 7.75 (d, 2 H, J = 8.0Hz), Method B 7.55 (d, 2 H, J = 8.4 Hz), 7.5 (d, 2 H, J = 8.0 Hz), 6.86(s, 1 H), 6.44 (s, 1 H), 4.96 (d, 1 H, J = 15.6 Hz), 4.36 (dd, 1 H, J =5.6 Hz, 6.0 Hz), 1.99 (m, 1 H), 1.29 (m, 1 H), 1.06 (m, 1 H), 0.77 (d, 3H, J = 6.8 Hz), 0.74 (d, 3 H, J = 6.8 Hz). 265 1-Method A white 481.011.81 481.3 ¹H NMR (CDCl₃) δ 7.61 (A or ABq, solid min 2 H, J = 8.8 Hz),7.42 (B of ABq, 2 H, Method A J = 8.8 Hz), 7.27 (A of ABq, 2 H, J = 8.4Hz), 7.19 (B of ABq, 2 H, J = 8.4 Hz), 6.21 (bs, 1 H), 5.19 (bs, 1 H),4.52 (A of ABq, 1 H, J = 15.5 Hz, 1 H), 4.39 (B of ABq, 1 H, J = 15.5Hz, 1 H), 4.30 (t, 1 H, J = 7.3 Hz), 4.14 (q, 2 H, J = 7.1 Hz), 3.58 (s,2 H, 1.86-1.76 (m, 1 H), 1.36-1.27 (m, 1 H), 1.14 (t, 3 H, J = 7.1 Hz),1.23-1.13 (m, 1 H), 0.76 (d, 3 H, J = 6.2 Hz), 0.66 (d, 3 H, J = 6.6Hz). 266 8 white 570.16 1.17 570.39 ¹H NMR, 400 Hz, (CDCl₃) δ 8.21 (d,foam min 2 H, J = 4.0 Hz), 8.02 (d, 2 H, J = 8.0 Hz), Method A 7.59 (d,2 H, J = 8.0 Hz), 7.39-7.33 (m, 4 H), 6.83 (d, 2 H, J = 4.0 Hz), 6.23(s, br, 1 H), 5.34 (s, br, 1 H), 4.60 (d, 1 H, J_(ab) = 16 Hz), 4.39 (d,1 H, J_(ab) = 16 Hz), 3.57 (s, 2 H), 3.27-3.15 (m, 5 H), 2.58-2.45 (m, 4H), 1.94 (m, 1 H), 1.60 (m, 2 H), 0.98 (d, 3 H, J = 7.0 Hz), 0.94 (d, 3H, J = 7.0 Hz) 267 8 white 508.08 1.28 508.21 ¹H NMR, 400 Hz, (CDCl₃) δ7.69 (d, foam min 2 H, J = 8.0 Hz), 7.63 (d, 2 H, J = 8.0 Hz), Method A7.43-7.36 (m, 4 H), 6.27 (s, br, 1 H), 5.39 (s, br, 1 H), 4.59 (d, 1 H,J_(ab) = 16 Hz), 4.36 (d, 1 H, J_(ab) = 16 Hz), 2.83 (m, 1 H), 2.41 (m,2 H), 2.18 (m, 1 H), 1.95 (m, 1 H), 1.85 (m, 1 H), 1.76-1.52 (m, 5 H),0.98 (d, 3 H, J = 7.0 Hz), 0.94 (d, 3 H, J = 7.0 Hz) 268 8 white 508.081.26 508.18 ¹H NMR, 400 Hz, (CDCl₃) δ 7.72 (d, foam min 2 H, J = 8.0Hz), 7.65 (d, 2 H, J = 8.0 Hz), Method A 7.45 (d, 2 H, J = 8.0 Hz), 7.38(d, 2 H, J = 8.0 Hz), 6.27 (s, br, 1 H), 5.39 (s, br, 1 H), 4.59 (d, 1H, J_(ab) = 16 Hz), 4.36 (d, 1 H, J_(ab) = 16 Hz), 3.77 (m, 1 H), 3.47(s, 2 H), 3.25 (t, 1 H, J = 6.0 Hz), 2.80 (m, 4 H), 1.95 (m, 1 H),1.77-1.50 (m, 6 H), 0.98 (d, 3 H, J = 7.0 Hz), 0.94 (d, 3 H, J = 7.0 Hz)269 8 white 437.99 1.28 438.16 ¹H NMR, 400 Hz, (CDCl₃) δ 7.71 (d, foammin 2 H, J = 8.0 Hz), 7.55 (d, 2 H, J = 8.0 Hz), Method A 7.43 (d, 2 H,J = 8.0 Hz), 7.37 (d, 2 H, J = 8.0 Hz), 6.35 (s, br, 1 H), 5.87 (s, br,1 H), 4.76 (d, 1 H, J_(ab) = 16 Hz), 4.30 (d, 1 H, J_(ab) = 16 Hz), 3.54(s, 5 H), 3.25 (t, 1 H, J = 6.0 Hz), 1.94 (m, 1 H), 1.60 (m, 2 H), 1.18(s, br, NH), 0.98 (d, 3 H, J = 7.0 Hz), 0.94 (d, 3 H, J = 7.0 Hz) 270 8white 468.02 1.28 468.16 ¹H NMR, 400 Hz, (CDCl₃) δ 7.72 (d, solid min 2H, J = 8.0 Hz), 7.67 (d, 2 H, J = 8.0 Hz), Method A 7.38 (d, 2 H, J =8.0 Hz), 7.33 (d, 2 H, J = 8.0 Hz), 6.35 (s, br, 1 H), 5.85 (s, br, 1H), 4.24-4.12 (m, 4 H), 3.67 (s, 2 H), 3.24 (t, 1 H, J = 6.0 Hz), 3.06(t, 2 H, J = 6.0 Hz), 2.60 (s, br, NH), 1.95 (m, 1 H), 1.68-1.52 (m, 2H), 0.98 (d, 3 H, J = 7.0 Hz), 0.94 (d, 3 H, J = 7.0 Hz) 271 8 clear482.05 1.31 482.18 ¹H NMR, 400 Hz, (CDCl₃) δ 7.79 (d, glass min 2 H, J =8.0 Hz), 7.69 (d, 2 H, J = 8.0 Hz), Method A 7.38 (d, 2 H, J = 8.0 Hz),7.33 (d, 2 H, J = 8.0 Hz), 6.35 (s, br, 1 H), 5.85 (s, br, 1 H), 4.60(d, 1 H, J_(ab) = 16 Hz), 4.43 (d, 1 H, J_(ab) = 16 Hz), 3.67 (s, 2 H),3.61 (t, 2 H, J = 6.0 Hz), 3.35 (s, 3 H), 3.29- 3.24 (m, 3 H), 1.94 (m,1 H), 1.62 (m, 2 H), 0.98 (d, 3 H, J = 7.0 Hz), 0.94 (d, 3 H, J = 7.0Hz) 272 9 white 523.1 1.30 523.40 ¹H NMR, 400 Hz, (CDCl₃) δ 8.02 (d,solid min 2 H, J = 8.0 Hz), 7.71 (d, 2 H, J = 8.0 Hz), Method A 7.37 (d,2 H, J = 8.0 Hz), 7.28 (d, 2 H, J = 8.0 Hz), 6.23 (s, br, 1 H), 5.51 (s,br, 1 H), 4.46 (s, 2 H), 4.70 (d, 1 H, J_(ab) = 16 Hz), 4.33 (d, 1 H,J_(ab) = 16 Hz), 3.25 (t, 1 H, J = 16 Hz), 2.69 (s, 3 H), 2.63 (s, 2 H),2.20 (s, 6 H), 1.95 (m, 1 H), 1.60 (m, 2 H), 0.98 (d, 3 H, J = 7.0 Hz),0.94 (d, 3 H, J = 7.0 Hz) 273 16 white 436.96 1.43 437.13 ¹H NMR (CDCl₃,300 MHz) δ 7.87 solid min (d, 2 H, J = 8.4), 7.67 (dd, 2 H, J = Method B1.8, 8.7), 7.42-7.46 (m, 4 H), 6.21 (br s, 1 H), 5.28 (br s, 1 H), 4.64(d, 1 H, J = 15.9), 4.45 (d, 1 H, J = 15.9), 4.31 (t, 1 H, J = 6.6),2.58 (s, 3 H), 1.73- 1.80 (m, 1 H), 1.25-1.35 (m, 1 H), 1.05-1.14 (m, 1H), 0.74 (d, 3 H, J = 6.5), 0.65 (d, 3 H, J = 6.6). 274 17 yellow 549.141.38 549.16 ¹H NMR, 400 Hz, (CDCl₃) δ 7.69 (d, foam min 2 H, J = 8.0Hz), 7.63 (d, 2 H, J = 8.0 Hz), Method A 7.38 (d, 2 H, J = 8.0 Hz), 7.23(d, 2 H, J = 8.0 Hz), 6.25 (s, br, 1 H), 5.35 (s, br, 1 H), 4.75 (d, 1H, J_(ab) = 16 Hz), 4.38 (d, 1 H, J_(ab) = 16 Hz), 3.25 (t, 1 H, J = 6.0Hz), 2.65 (t, 2 H, J = 6.0 Hz), 2.56-2.44 (m, 6 H), 1.95 (m, 1 H),1.68-1.45 (m, 8 H), 0.98 (d, 3 H, J = 7.0 Hz), 0.94 (d, 3 H, J = 7.0 Hz)275 17 clear 564.15 1.21 564.32 ¹H NMR, 400 Hz, (CDCl₃) δ 9.30 (s, glassmin 1 H, NH), 8.02 (d, 2 H, J = 8.0 Hz), 7.61 Method A (d, 2 H, J = 8.0Hz), 7.36 (d, 2 H, J = 8.0 Hz), 7.23 (d, 2 H, J = 8.0 Hz), 6.25 (s, br,1 H), 5.33 (s, br, 1 H), 4.72 (d, 1 H, J_(ab) = 16 Hz), 4.48 (d, 1 H,J_(ab) = 16 Hz), 3.25 (t, 1 H, J = 6.0 Hz), 2.65-2.38 (m, 12 H), 2.28(s, 2 H), 1.95 (m, 1 H), 1.59 (m, 2 H), 0.98 (d, 3 H, J = 7.0 Hz), 0.94(d, 3 H, J = 7.0 Hz) 276 17 tan 509.07 1.33 509.17 ¹H NMR, 400 Hz,(CDCl₃) δ 9.31 (s, foam min 1 H, NH), 8.02 (d, 2 H, J = 8.0 Hz), 7.63Method A (d, 2 H, J = 8.0 Hz), 7.36 (d, 2 H, J = 8.0 Hz), 7.23 (d, 2 H,J = 8.0 Hz), 6.25 (s, br, 1 H), 5.34 (s, br, 1 H), 4.71 (d, 1 H, J_(ab)= 16 Hz), 4.48 (d, 1 H, J_(ab) = 16 Hz), 3.25 (t, 1 H, J = 6.0 Hz), 2.66(t, 2 H, J = 8.0 Hz), 2.56 (t, 2 H, J = 8.0 Hz), 2.38 (s, 6 H), 1.95 (m,1 H), 1.60 (m, 2 H), 0.98 (d, 3 H, J = 7.0 Hz), 0.94 (d, 3 H, J = 7.0Hz) 277 9 tan 515.04 1.47 515.13 ¹H NMR, 400 Hz, (CDCl₃) δ 8.95 (s, foammin br, NH), 8.67 (d, 1 H, J = 8.0 Hz), 8.17 Method A (d, 1 H, J = 8.0Hz), 8.02 (d, 2 H, J = 8.0 Hz), 7.77 (d, 2 H, J = 8.0 Hz), 7.57 (m, 4H), 7.38 (d, 2 H, J = 8.0 Hz), 6.27 (s, br, 1 H), 5.39 (s, br, 1 H),4.72 (d, 1 H, J_(ab) = 16 Hz), 4.30 (d, 1 H, J_(ab) = 16 Hz), 3.25 (t, 1H, J = 6.0 Hz), 1.95 (m, 1 H), 1.60 (m, 2 H), 0.98 (d, 3 H, J = 7.0 Hz),0.94 (d, 3 H, J = 7.0 Hz) 278 7 white 507.06 2.44 509.20 ¹H NMR (CDCl₃,500 MHz) δ 8.66 solid min (br s, 2 H), 7.80 (d, 1 H, J = 8.6), 7.73Method C (d, 2 H, J = 8.5), 7.51 (d, 2 H, J = 7.6), 7.41 (br s, 1 H),6.64 (br s, 1 H), 5.35 (br s, 1 H), 4.70 (br s, 1 H), 4.10 (br s, 1 H),3.71 (br s, 1 H), 3.33 (br s, 1 H), 3.02 (dd, 2 H, J = 4.8, 16),2.70-2.85 (br s, 1 H), 1.50-2.09 (m, 5 H), 1.18- 1.33 (m, 4 H), 0.73 (d,3 H, J = 6.7), 0.68 (d, 3 H, J = 6.5).. 279 7 white 549.14 2.76 549.07¹H NMR (CDCl₃, 500 MHz) δ 7.74 solid min (dd, 2 H, J = 1.7, 6.7), 7.51(dd, 2 H, J = Method C 2.2, 6.9), 7.34 (d, 2 H, J = 8.0), 6.70 (br s, 1H), 6.60 (br s, 1 H), 5.30 (br s, 1 H), 4.13 (dd, 1 H, J = 5.5, 10),3.35 (dd, 1 H, J = 11, 14), 3.00 (s, 6 H), 2.85 (s, 2 H), 1.80-2.00 (m,3 H), 1.50-1.70 (m, 1 H), 1.10-1.30 (m, 4 H), 0.80-0.90 (m, 1 H), 0.745(d, 3 H, J = 6.7), 0.67 (d, 3 H, J = 6.5). 280 7 white 574.07 3.03574.03 ¹H NMR (CDCl₃, 500 MHz) δ 7.73 solid Method C (d, 2 H, J = 8.2),7.65 (d, 2 H, J = 7.9), 7.51 (d, 2 H, J = 8.9), 7.48 (d, 2 H, J = 7.6),6.65 (br s, 1 H), 5.45 (br s, 1 H), 4.71 (br s, 1 H), 4.13 (br s, 1 H),3.65 (br s, 1 H), 3.30 (br s, 1 H), 2.97 (d, 2 H J = 12), 2.65-2.86 (m,1 H), 1.45- 2.07 (m, 6 H), 0.98-1.85 (m, 3 H), 0.73 (br, s, 3 H), 0.67(br, s, 3 H). 281 7 white 470.04 2.78 470.03 H NMR (CDCl₃, 500 MHz) δ7.72 (d, solid min 2 H, J = 8.5), 7.50 (d, 2 H, J = 8.6), Method C6.78-6.90 (m, 1 H), 6.55-6.65 (m, 1 H), 6.23 (dd, 1 H, J = 1.5, 15),5.33- 5.60 (m, 1 H), 4.50-4.75 (m, 1 H), 4.09-4.20 (m, 1 H), 3.90-4.05(m, 1 H), 2.80-3.25 (m, 3 H), 2.40-2.75 (m, 1 H), 1.50-2.00 (m, 8 H),1.00- 1.40 (m, 3 H), 0.73 (br, s, 3 H), 0.67 (br, s, 3 H). 282 7 white506.07 2.86 508.03 ¹H NMR (CDCl₃, 500 MHz) δ 7.73 solid min (d, 2 H, J =8.5), 7.51 (d, 2 H, J = 8.5), Method C 7.38 (br s, 4 H), 6.65 (br s, 1H), 5.35 (br s, 1 H), 4.71 (br s, 1 H), 4.14 (br s, 1 H), 3.76 (br s, 1H, 3.30 (br s, 1 H), 2.60-3.05 (m, 3 H), 0.99-2.05 (m, 10 H), 0.73 (d, 3H, J = 7.8), 0.67 (d, 3 H, J = 7.8). 283 7 white 517.09 1.34 517.19 ¹HNMR (CDCl₃, 500 MHz) δ 7.72 solid min (d, 2 H, J = 8.5), 7.50-7.65 (m, 2H), Method A 7.50 (d, 2 H, J = 7.0), 7.35-7.45 (m, 2 H), 6.67 (s, 1 H),5.32 (s, 1 H), 4.14 (dd, 1 H, J = 5.0, 9.0), 3.52 (br s, 1 H), 3.28 (t,1 H, J = 14), 2.97 (dd, 1 H, J = 3.5, 14), 2.82 (br s, 1 H), 1.00-2.00(m, 10 H), 0.71 (d, 3 H, J = 6.5), 0.66 (d, 3 H, J = 6.5). 284 7 white550.12 2.87 550.06 ¹H NMR (CDCl₃, 500 MHz) δ 7.72 solid min (d, 2 H, J =8.6), 7.50 (d, 2 H, J = 8.5), Method C 7.13 (d, 2 H, J = 8.5), 6.85 (brs, 2 H), 6.63 (d, 1 H, J = 33), 5.41 (br s, 1 H), 4.62 (t, 1 H, J = 14),4.10-4.17 (m, 1 H), 3.75-3.90 (m, 4 H), 3.65 (s, 3 H), 3.14-3.30 (m, 1H), 2.80-2.95 (m, 2 H), 2.43-2.60 (m, 1 H), 1.45-2.00 (m, 4 H),1.15-1.30 (m, 2 H), 0.71 (dd, 3 H, J = 7.6, 8.4), 0.65 (dd, 3 H, J =6.0, 8.0). 285 7 white 541.50 2.76 540.98 ¹H NMR (CDCl₃, 500 MHz) δ 8.43solid min (s, 1 H), 7.73 (d, 2 H, J = 8.5), 7.70 (d, Method C 1 H, J =2.4, 8.4), 7.51 (d, 2 H, J = 8.6), 7.87 (d, 1 H, J = 8.2), 6.63 (br s, 1H), 5.35 (br s, 1 H), 4.68 (br s, 1 H), 4.15 (dd, 1 H, J = 4.9, 9.8),3.71 (br s, 1 H), 3.31 (br s, 1 H), 3.00 (dd, 2 H, J = 4.8, 14),2.65-2.86 (m, 1 H), 1.77- 2.07 (m, 3 H), 1.6-1.76 (m, 1 H), 1.00- 1.86(m, 3 H), 0.85-0.93 (m, 1 H), 0.73 (d, 3 H, J = 6.7), 0.67 (d, 3 H, J =6.7). 286 7 white 545.11 1.36 545.16 ¹H NMR (CDCl₃, 500 MHz) δ 8.11solid min (d, 2 H, J = 8.6), 7.75 (d, 2 H, J = 8.6), Method A 7.73 (d, 2H, J = 8.9), 7.50 (d, 2 H, J = 8.9), 6.65 (br s, 1 H), 5.38 (br s, 1 H),4.14 (dd, 1 H, J = 5.5, 9.5), 3.80 (br s, 1 H), 3.27 (dd, 1 H, J = 10,14), 2.97 (dd, 2 H, J = 4.6, 14), 1.17-2.00 (m, 11 H), 0.75-0.81 (m, 1H), 0.73 (d, 3 H, J = 6.4), 0.67 (d, 3 H, J = 6.7). 287 12 white 453.011.81 453.16 ¹H NMR (CDCl₃, 300 MHz) δ 7.61 solid min (d, 2 H, J = 8.7),7.40 (d, 2 H, J = 8.7), Method A 7.37 (d, 2 H, J = 8.4), 7.26 (d, 2 H, J= 8.4), 6.28 (br s, 1 H), 5.25 (br s, 1 H), 4.49 (d, 1 H, J = 15.9),4.41 (d, 1 H, J = 15.9), 4.33 (t, 1 H, J = 6.6), 1.73- 1.80 (m, 1 H),1.55 (s, 6 H), 1.28-1.35 (m, 1 H), 1.20-1.25 (m, 1 H), 0.77 (d, 3 H, J =6.5), 0.66 (d, 3 H, J = 6.6). 288 7 white 493.07 1.25 493.23 ¹H NMR(CDCl₃, 500 MHz) δ 8.51 solid min (s, 2 H), 7.73 (d, 2 H, J = 8.5), 7.50(d, Method A 2 H, J = 8.5), 6.67 (s, 1 H), 5.83 (s, 1 H), 4.15 (dd, 1 H,J = 5.2, 8.9), 3.50 (br s, 2 H), 3.25 (dd, 1 H, J = 8.5, 14), 2.75-3.05(m, 3 H), 1.60-2.10 (m, 6 H), 1.10-1.40 (m, 4 H), 0.75-0.85 (m, 1 H),0.72 (d, 3 H, J = 6.4), 0.67 (d, 3 H, J = 6.7). 289 2 yellow 493.07 0.93493.2 ¹H NMR (CDCl₃) δ 7.67 (d, 2 H, solid min J = 7.0 Hz), 7.44 (d, 2H, J = 7.0 Hz), Method B 7.19 (d, 2 H, J = 8.0 Hz), 6.46 (d, 2 H, J =8.0 Hz), 6.21 (s, br, 1 H), 5.17 (s, br, 1 H), 4.31 (dd, 2 H, J = 50 Hz,15 Hz), 4.15-4.22 (m, 1 H), 3.84-3.87 (m, 4 H), 3.91-3.99 (m, 1 H),3.51- 3.54 (m, 3 H), 3.22-3.26 (m, 1 H), 2.75 (s, 3 H), 2.72 (s, 3 H),2.23-2.36 (m, 2 H), 1.91-1.98 (m, 1 H), 1.32- 1.40 (m, 1 H), 0.81-1.04(m, 2 H), 0.73 (t, 3 H, 7.2 Hz). 290 2 tan 464.03 1.16 464.2 ¹H NMR(CDCl₃) δ 7.62 (d, 2 H, solid min J = 8.8 Hz), 7.40 (d, 2 H, J = 8.0Hz), Method B 7.11-7.20 (m, 2 H), 6.79-6.88 (m, 2 H), 6.20 (s, br, 1 H),5.13 (s, br, 1 H), 4.30 (dd, 2 H, J = 50 Hz, 15 Hz), 4.13-4.21 (m, 1 H),3.10-3.19 (m, 4 H), 1.92-1.95 (m, 1 H), 1.39-1.90 (m, 8 H), 1.22-1.26(m, 1 H), 0.97- 1.05 (m, 2 H), 0.73 (t, 3 H, J = 8.0 Hz). 291 11 orange522.11 1.52 522.1 ¹H NMR (DMSO) δ 7.78 (d, 2 H, J = solid min 8.4 Hz),7.58 (d, 2 H, J = 8.8 Hz), 7.47 Method E (s, br, 1 H), 7.27 (d, 2 H, J =8.4 Hz), 7.00 (s br, 1 H), 6.85 (d, 2 H, J = 8.8 Hz), 4.63 (dd, 2 H, J =16 Hz, 38 Hz), 4.34 (m, 1 H), 4.03 (s, 2 H), 2.63 (m, 2 H), 2.42 (m, 3H), 1.39 (m, 10 H), 0.80 (d, 3 H, J = 6.0 Hz), 0.50 (d, 3 H, J = 6.0 Hz)292 11 white 481.18 1.46 482.06 ¹H NMR (DMSO) δ 7.79 (d, 2 H, J = solidmin 8.8 Hz), 7.60 (d, 2 H, J = 8.8 Hz), 7.49 Method E (s, br, 1 H), 7.35(d, 2 H, J = 8.4 Hz), 7.01 (s br, 1 H), 6.94 (d, 2 H, J = 8.8 Hz), 4.68(dd, 2 H, J = 16 Hz, 53 Hz), 4.35 (m, 1 H), 4.28 (t, 2 H, J = 4.8 Hz),3.34 (m, 2 H), 2.86 (s, 6 H), 1.33 (m, 3 H), 0.80 (d, 3 H, J = 6.0 Hz),0.50 (d, 3 H, J = 6.0 Hz) 293 11 white 509.21 1.52 M + Na ¹H NMR (DMSO)δ 7.79 (d, 2 H, J = residue min 532.03 8.4 Hz), 7.60 (d, 2 H, J = 8.4Hz), 7.48 Method E (s, br, 1 H), 7.35 (d, 2 H, J = 8.8 Hz), 7.01 (s br,1 H), 6.94 (d, 2 H, J = 8.8 Hz), 4.68 (dd, 2 H, J = 17 Hz, 54 Hz), 4.35(m, 1 H), 4.28 (t, 2 H, J = 4.8 Hz), 3.51 (m, 3 H), 3.21 (m, 3 H), 1.29(m, 9 H), 0.80 (d, 3 H, J = 6.0 Hz), 0.50 (d, 3 H, J = 6.0 Hz) 294 11light 544.12 1.78 544.13 ¹H NMR (DMSO) δ 7.78 (d, 2 H, J = brown min 8.9Hz), 7.57 (d, 2 H, J = 8.0 Hz), 7.45 solid Method E (s, br, 1 H), 7.27(d, 2 H, J = 8.0 Hz), 7.17 (t, 2 H, J = 8.9 Hz) 7.00 (s br, 1 H), 6.84(d, 2 H, J = 8.0 Hz), 6.75 (d, 2 H, J = 8.0 Hz), 6.62 (t, 1 H, J = 8.0Hz), 4.65 (dd, 2 H, J = 17 Hz, 41 Hz), 4.34 (m, 1 H), 4.10 (t, 2 H, J =5.5 Hz), 3.71 (t, 2 H, J = 7.9 Hz), 2.96 (m, 3 H), 1.32 (m, 3 H), 0.79(d, 3 H, J = 6.0 Hz), 0.49 (d, 3 H, J = 6.0 Hz) 295 11 white 558.14 1.62558.10 ¹H NMR (DMSO) δ 7.80 (d, 2 H, J = powder min 8.6 Hz), 7.60 (d, 2H, J = 8.6 Hz), 7.54 Method E (m, 2 H), 7.49 (m, 4 H), 7.34 (d, 2 H, J =8.6 Hz) 7.01 (s br, 1 H), 6.93 (d, 2 H, J = 8.6 Hz), 4.68 (dd, 2 H, J =17.0 Hz, 54 Hz), 4.47 (m, 1 H), 4.36 (m, 4 Hz), 3.50 (m, 2 H), 2.80 (s,3 H), 1.34 (m, 3 H), 0.80 (d, 3 H, J = 6.0 Hz), 0.51 (d, 3 H, J = 6.0Hz) 296 11 white 508.08 1.49 508.07 ¹H NMR (DMSO) δ 7.79 (d, 2 H, J =powder min 8.6 Hz), 7.61 (d, 2 H, J = 8.6 Hz), 7.49 Method E (s, br,1H), 7.35 (d, 2 H, J = 8.6 Hz), 7.00 (s br, 1 H), 6.94 (d, 2 H, J = 8.6Hz), 4.68 (dd, 2 H, J = 17.0 Hz, 53 Hz), 4.35 (m, 1 H), 4.27 (m, 2 H),3.59 (m, 4 H), 3.13 (m, 2 H), 2.03 (m, 2 H), 1.89 (m, 2 H), 1.34 (m, 3H), 0.80 (d, 3 H, J = 6.0 Hz), 0.52 (d, 3 H, J = 6.0 Hz) 297 11 off524.08 1.46 524.09 ¹H NMR (DMSO) δ 7.78 (d, 2 H, J = white min 8.9 Hz),7.57 (d, 2 H, J = 8.0 Hz), 7.45 solid Method E (s, br, 1 H), 7.27 (d, 2H, J = 8.0 Hz), 7.17 (t, 2 H, J = 8.9 Hz) 7.00 (s br, 1 H), 6.84 (d, 2H, J = 8.0 Hz), 6.75 (d, 2 H, J = 8.0 Hz), 6.62 (t, 1 H, J = 8.0 Hz),4.65 (dd, 2 H, J = 17 Hz, 41 Hz), 4.34 (m, 1 H), 4.10 (t, 2 H, J = 5.5Hz), 3.71 (t, 2 H, J = 7.9 Hz), 2.96 (m, 3 H), 1.32 (m, 3 H), 0.79 (d, 3H, J = 6.0 Hz), 0.49 (d, 3 H, J = 6.0 Hz) 298 11 white 540.15 1.52540.06 ¹H NMR (DMSO) δ 7.80 (d, 2 H, J = solid min 8.8 Hz), 7.60 (d, 2H, J = 8.0 Hz), 7.48 Method E (s br, 1 H), 7.35 (d, 2 H, J = 8.8 Hz),7.01 (s br, 1 H) 6.95 (d, 2 H, J = 8.8 Hz), 4.68 (dd, 2 H, J = 16.4 Hz,55 Hz), 4.34 (m, 3 H), 3.79 (m, 2 H), 3.58 (m, 2 H), 3.27 (m, 2 H), 3.02(m, 2 H), 2.89 (m, 2 H), 1.34 (m, 3 H), 0.80 (d, 3 H, J = 6.0 Hz), 0.52(d, 3 H, J = 6.0 Hz) 299 11 light 537.13 1.43 537.13 ¹H NMR (DMSO) δ7.79 (d, 2 H, J = orange min 8.8 Hz), 7.59 (d, 2 H, J = 8.0 Hz), 7.48solid Method E (s br, 1 H), 7.31 (d, 2 H, J = 8.8 Hz), 7.00 (s br, 1 H)6.88 (d, 2 H, J = 8.8 Hz), 4.66 (dd, 2 H, J = 16.4 Hz, 49 Hz), 4.35 (m,1 H), 4.11 (m, 2 H), 3.18 (m, 9 H), 2.78 (m, 3 H), 2.63 (m, 1 H), 1.34(m, 3 H), 0.80 (d, 3 H, J = 6.0 Hz), 0.51 (d, 3 H, J = 6.0 Hz) 300 2 tan507.10 1.19 507.2 ¹H NMR (CDCl₃) δ 7.63 (d, 2 H, solid min J = 8.0 Hz),7.41 (d, 2 H, J = 8.0 Hz), Method B 7.13-7.24 (m, 2 H), 6.74-6.80 (m, 2H), 6.23 (s, br, 1 H), 5.13 (s, br, 1 H), 4.37 (dd, 2 H, J = 50 Hz, 15Hz), 4.11-4.19 (m, 1 H), 3.77-3.81 (m, 1 H), 3.44 (s, 6 H), 3.06-3.13(m, 8 H), 1.93-1.96 (m, 1 H), 1.25-1.29 (m, 1 H), 0.95-1.09 (m, 2 H),0.71 (t, 3 H, J = 8.0 Hz). 301 10 yellow 465.02 1.22 465.25 ¹H NMR(CDCl₃) TFA salt: δ 8.07 foam Method B (s, 1 H), 7.91 (d, 1 H, J = 9.6Hz), 7.74 (d, 2 H, J = 6.8 Hz), 7.52 (d, 2 H, J = 6.8 Hz), 6.64 (d, 1 H,J = 9.6 Hz), 6.36 (s, 1 H), 5.77 (s, 1 H), 4.52 (d, 1 H, J = 16.0 Hz),4.28 (dd, 1 H, J = 5.6 Hz, 6.0 Hz), 4.21 (d, 1 H, J = 16.0 Hz), 3.62 (m,4 H), 2.13 (m, 4 H), 1.84 (m, 1 H), 1.32 (m, 1 H), 0.96 (m, 1 H), 0.79(d, 3 H, J = 6.8 Hz), 0.72 (d, 3 H, J = 6.8 Hz). 302 10 yellow 479.051.28 479.06 ¹H NMR (CDCl₃) TFA salt: δ 8.01 foam Method B (s, 1 H), 7.95(d, 1 H, J = 9.6 Hz), 7.75 (d, 2 H, J = 8.0 Hz), 7.50 (d, 2 H, J = 8.4Hz), 6.88 (d, 1 H, J = 9.6 Hz), 6.43 (s, 1 H), 6.04 (s, 1 H), 4.53 (d, 1H, J = 16.0 Hz), 4.28 (dd, 1 H, J = 5.6 Hz, 6.0 Hz), 4.20 (d, 1 H, J =16.0 Hz), 3.65 (m, 4 H), 1.82 (m, 1 H), 1.74 (m, 6 H), 1.31 (m, 1 H),0.95 (m, 1 H), 0.78 (d, 3 H, J = 6.4 Hz), 0.71 (d, 3 H, J = 6.4 Hz). 30310 white 481.02 1.16 481.05 ¹H NMR (CDCl₃) TFA salt: δ 8.25 solid MethodB (s, 1 H), 8.06 (d, 1 H, J = 9.6 Hz), 7.74 (d, 2 H, J = 8.0 Hz), 7.54(d, 2 H, J = 8.0 Hz), 6.91 (d, 1 H, J = 9.6 Hz), 6.55 (s, 1 H), 6.28 (s,1 H), 4.61 (d, 1 H, J = 16.0 Hz), 4.28 (dd, 1 H, J = 5.2 Hz, 6.2 Hz),4.21 (d, 1 H, J = 16.0 Hz), 3.87 (m, 4 H), 3.67 (m, 4 H), 1.84 (m, 1 H),1.27 (m, 1 H), 0.93 (m, 1 H), 0.76 (d, 3 H, J = 6.4 Hz), 0.72 (d, 3 H, J= 6.4 Hz). 304 10 brown 493.07  1.357 493.04 ¹H NMR (CDCl₃) TFA salt: δ8.04 solid Method B (s, 1 H), 7.93 (d, 1 H, J = 9.2 Hz), 7.73 (d, 2 H, J= 8.0 Hz), 7.50 (d, 2 H, J = 8.0 Hz), 6.69 (d, 1 H, J = 9.2 Hz), 6.38(s, 1 H), 5.98 (s, 1 H), 4.50 (d, 1 H, J = 16.0 Hz), 4.30 (dd, 1 H, J =5.6 Hz, 6.0 Hz), 4.22 (d, 1 H, J = 16.0 Hz), 4.20 (m, 2 H), 3.87 (m, 4H), 2.24 (m, 2 H), 1.90 (m, 2 H), 1.84 (m, 1 H), 1.36 (d, 3 H, J = 2.0Hz), 1.34 (d, 3 H, J = 2.0 Hz), 1.32 (m, 1 H), 0.98 (m, 1 H), 0.79 (d, 3H, J = 6.4 Hz), 0.72 (d, 3 H, J = 6.4 Hz). 305 7 white 513 1.03 513.36¹H NMR (CDCl₃, 500 MHz) δ 7.72 solid min (d, 2 H, J = 8.5), 7.50 (d, 2H, J = 7.0), Method A 6.65 (s, 1 H), 6.35 (s, 1 H), 4.14 (dd, 1 H, J =5.5, 9.0), 3.25 (dd, 1 H, J = 10, 14), 1.35-2.95 (m, 24 H), 1.15- 1.30(m, 3 H), 0.72 (d, 3 H, J = 6.5), 0.67 (d, 3 H, J = 6.7). 306 7 white487 1.43 487.019 ¹H NMR (CDCl₃, 300 MHz) δ 7.72 solid min (d, 2 H, J =8.4), 7.51 (d, 2 H, J = 8.7), Method A 6.67 (d, 1 H, J = 24.3), 5.40 (d,1 H, J = 12, 6), 4.54 (br s, 1 H), 3.90-4.20 (m, 4 H), 3.40-3.55 (m, 2H), 3.05- 3.35 (m, 2 H), 2.85-3.05 (m, 2 H), 2.40-2.60 (m, 1 H), 2.35(d, 6 H, J = 8.1), 0.60-1.95 (m, 11 H). 307 1-Method A clear 444.03 1.28444.04 ¹H NMR (CDCl₃) δ 7.72 (d, oil min J = 6.8 Hz, 2 H), 7.52 (d, J =6.8 Hz, 2 H), Method B 6.75 (s, br, 1 H), 5.79 (s, br, 1 H), 4.14 (dd, J= 9.6 Hz, 4.8 Hz, 1 H), 3.23 (dd, J = 14.4 Hz, 10.0 Hz, 1 H), 3.12 (m, 1H), 2.92 (dd, J = 14.4 Hz, 4.8 Hz, 1 H), 2.77 (m, 6 H), 2.09 (m, 2 H),1.83 (m, 1 H), 1.71 (m, 1 H), 0.75- 1.52 (m, 8 H), 0.73 (d, J = 6.8 Hz,3 H), 0.67 (d, J = 6.8 Hz, 3 H). 308 23 tan 495.04 1.31 495.14 ¹H NMR(CDCl₃) δ 8.85 (s, foam min 1 H, NH), 8.02 (d, 2 H, J = 8.0 Hz), 7.75Method A (d, 2 H, J = 8.0 Hz), 7.38 (d, 2 H, J = 8.0 Hz), 7.29 (d, 2 H,J = 8.0 Hz), 6.23 (s, br, 1 H), 5.39 (s, br, 1 H), 4.62 (m, 4 H), 3.25(t, 1 H, J = 6.0 Hz), 2.95 (s, 6 H), 1.95 (m, 1 H), 1.60 (m, 2 H), 0.98(d, 3 H, J = 7.0 Hz), 0.94 (d, 3 H, J = 7.0 Hz) 309 23 tan 535.11 1.34535.29 ¹H NMR, 400 Hz, (CDCl₃) δ 8.85 (s, foam min 1 H, NH), 8.02 (d, 2H, J = 8.0 Hz), 7.78 Method A (d, 2 H, J = 8.0 Hz), 7.38 (d, 2 H, J =8.0 Hz), 7.30 (d, 2 H, J = 8.0 Hz), 6.25 (s, br, 1 H), 5.36 (s, br, 1H), 4.62 (m, 4 H), 3.25 (t, 1 H, J = 6.0 Hz), 2.42 (m, 4 H), 1.95 (m, 1H), 1.68-1.38 (m, 8 H), 0.98 (d, 3 H, J = 7.0 Hz), 0.94 (d, 3 H, J = 7.0Hz) 310 23 tan 550.12 1.24 550.25 ¹H NMR, 400 Hz, (CDCl₃) δ 8.83 (s,foam min 1 H, NH), 8.02 (d, 2 H, J = 8.0 Hz), 7.78 Method A (d, 2 H, J =8.0 Hz), 7.38 (d, 2 H, J = 8.0 Hz), 7.30 (d, 2 H, J = 8.0 Hz), 6.20 (s,br, 1 H), 5.39 (s, br, 1 H), 4.71 (d, 1 H, J_(ab) = 16 Hz), 4.48 (d, 1H, J_(ab) = 16 Hz), 4.26 (s, 2 H), 3.25 (m, 1 H), 2.67 (m, 8 H), 2.40(s, 3 H), 1.95 (m, 1 H), 1.60 (m, 2 H), 0.98 (d, 3 H, J = 7.0 Hz), 0.94(d, 3 H, J = 7.0 Hz) 311 7 white 492.09 2.30 492.16 ¹H NMR (CDCl₃, 300MHz) δ 7.73 solid min (d, 2 H, J = 8.4), 7.48 (d, 2 H, J = 8.4), MethodC 7.15-7.38 (m, 5 H), 6.67 (s, 1 H), 5.37 (s, 1 H), 4.14 (dd, 1 H, J =5.4, 9.0), 3.47 (s, 2 H), 3.24 (dd, 1 H, J = 10, 14), 2.75-3.05 (m, 3H), 1.45-2.05 (m, 10 H), 0.75-0.90 (m, 1 H), 0.71 (d, 3 H, J = 6.6),0.65 (d, 3 H, J = 6.6). 312 7 white 529.15 2.27 529.16 ¹H NMR (CDCl₃,300 MHz) δ 7.73 solid min (d, 2 H, J = 8.7), 7.50 (d, 2 H, J = 8.7),Method C 6.65 (d, 1 H, J = 5.1), 4.55 (br s, 1 H), 4.05-4.30 (m, 1),3.57-3.95 (m, 1 H), 3.10-3.40 (m, 1 H), 2.40-3.00 (m, 12 H), 1.70-2.00(m, 3 H), 0.90-1.30 (m, 10 H), 0.60-0.75 (m, 6 H). 313 7 white 573.161.78 573.18 ¹H NMR (CDCl₃, 300 MHz) δ 7.72 solid min (d, 2 H, J = 7.8),7.50 (d, 2 H, J = 8.7), Method A 6.65 (d, 1 H, J = 14), 5.35 (s, 1 H),4.45-4.65 (m, 1 H), 3.67-4.25 (m, 3 H), 3.35-3.60 (m, 3 H), 3.10-3.25(m, 1 H), 2.80-3.10 (m, 2 H), 2.90 (s, 3 H), 0.95-2.00 (m, 7 H), 1.46(s, 9 H), 0.73 (br, s, 3 H), 0.67 (br, s, 3 H). 314 7 white 532.11 1.47532.19 ¹H NMR (CDCl₃, 300 MHz) δ 7.74 solid min (d, 2 H, J = 8.8), 7.50(d, 3 H, 8.8), Method A 7.17-7.27 (m, 3 H), 6.63 (s, 1 H), 5.60 (s, 1H), 4.13 (dd, 1 H, J = 5.5, 9.2), 3.80 (s, 2 H), 3.28 (dd, 1 H, J = 9.5,15), 2.80-305 (m, 3 H), 1.50-2.25 (m, 6 H), 1.15-1.45 (m, 5 H), 0.72 (d,3 H, J = 6.6), 0.66 (d, 3 H, J = 6.6). 315 7 white 444.04 2.11 444.13 ¹HNMR (CDCl₃, 300 MHz) δ 7.73 solid min (d, 2 H, J = 8.7), 7.8 (d, 2 H, J= 8.4), Method C 6.69 (br s, 1 H), 5.45 (br s, 1 H), 4.14 (dd, 1 H, J =10, 15), 3.15-3.35 (m, 1 H), 2.90-3.05 (m, 1 H), 2.75-2.90 (m, 1 H),2.60-2.75 (m, 1 H), 1.50- 2.25 (m, 6 H), 1.05-1.40 (m, 3 H), 1.00 (d, 6H, J = 11), 0.75-0.90 (m, 1 H), 0.71 (d, 3 H, J = 10), 0.66 (d, 3 H, J =10). 316 9 yellow 515.04 1.50 515.08 ¹H NMR, 400 Hz, (CDCl₃) δ 9.97 (s,foam min 1 H, NH), 8.82 (d, 2 H, J = 4.0 Hz), 8.02 Method A (d, 2 H, J =8.0 Hz), 7.76 (d, 2 H, J = 8.0 Hz), 7.73 (d, 2 H, J = 4.0 Hz), 7.46 (d,2 H, J = 8.0 Hz), 7.38 (d, 2 H, J = 8.0 Hz), 6.27 (s, br, 1 H), 5.39 (s,br, 1 H), 4.72 (d, 1 H, J_(ab) = 16 Hz), 4.30 (d, 1 H, J_(ab) = 16 Hz),4.26 (s, 2 H), 3.25 (t, 1 H, J = 6.0 Hz), 1.95 (m, 1 H), 1.60 (m, 2 H),0.98 (d, 3 H, J = 7.0 Hz), 0.94 (d, 3 H, J = 7.0 Hz) 317 2 dark 482.021.42 482.01 ¹H NMR (CDCl₃) δ 7.63 (d, 2 H, wax min J = 8.2 Hz), 7.42 (d,2 H, J = 8.2 Hz), Method B 6.71-7.08 (m, 3 H), 6.20 (s, br, 1 H), 5.15(s, br, 1 H), 4.27 (dd, 2H, J = 50 Hz, 15 Hz), 4.23- (t, 1 H, J = 7.0Hz), 2.99-3.10 (m, 4 H), 1.92- 1.95 (m, 1 H), 1.53-1.59 (m, 2 H),1.41-1.90 (m, 4 H), 1.21-1.24 (m, 1 H), 0.98-1.08 (m, 2 H) 0.74 (t, 3 H,J = 8.0 Hz). 318 2 dark 498.02 1.68 498.2 ¹H NMR (CDCl₃) δ 7.66 (d, 2 H,solid min J = 8.0 Hz), 7.42 (d, 2 H, J = 8.0 Hz), Method B 6.84-7.02 (m,3 H), 6.20 (s, br, 1 H), 5.22 (s, br, 1 H), 4.34 (dd, 2 H, J = 50 Hz, 15Hz), 4.19-4.25 (m, 1 H), 3.84-3.86 (m, 4 H), 3.15-3.17 (m, 1 H),3.03-3.06 (m, 4 H), 1.31-1.77 (m, 2 H), 0.95 (d, 3 H, J = 7.0 Hz), 0.83(d, 3 H, J = 7.0 Hz). 319 9 tan 515.04 1.77 515.15 ¹H NMR, 400 Hz,(CDCl₃) δ 9.90 (s, foam min 1 H, NH), 8.51 (d, 1 H, J = 4.0 Hz), 8.11Method A (d, 2 H, J = 8.0 Hz), 8.01 (d, 2 H, J = 8.0 Hz), 7.78 (m, 3 H),7.59 (d, 2 H, J = 8.0 Hz), 7.38 (d, 2 H, J = 8.0 Hz), 7.32 (t, 1 H, J =4.0 Hz), 6.27 (s, br, 1 H), 5.38 (s, br, 1 H), 4.71 (d, 1 H, J_(ab) = 16Hz), 4.31 (d, 1 H, J_(ab) = 16 Hz), 3.25 (t, 1 H, J = 6.0 Hz), 1.95 (m,1 H), 1.60 (m, 2 H), 0.98 (d, 3 H, J = 7.0 Hz), 0.94 (d, 3 H, J = 7.0Hz) 320 2 tan 511.06 1.12 511.2 ¹H NMR (d₆DMSO) δ 7.78 (d, 2 H, solidmin J = 8.2 Hz), 7.55 (d, 2 H, J = 8.2 Hz), Method B 7.02-7.14 (m, 3 H),6.80 (s, br, 1 H), 4.82 (s, br, 1 H), 3.58-4.63 (m, 2 H), 4.32-4.38 (m,1 H), 3.42-3.56 (m, 4 H), 3.16-3.21 (m, 1 H), 2.84 (s, 3 H), 2.49-2.51(m, 4 H), 1.85 (s, 3 H), 1.76-1.82 (m, 1 H), 1.21-1.33 (m, 2 H), 0.82(d, 3 H, J = 7.0 Hz), 0.56 (d, 3 H, J = 7.0 Hz). 321 7 white 486.08 2.22486.12 ¹H NMR (CDCl₃, 300 MHz) δ 7.73 solid min (d, 2 H, J = 8.5), 7.49(d, 2 H, J = 8.6), Method C 6.67 (s, 1 H), 5.35 (s, 1 H), 4.15 (dd, 1 H,J = 5.8, 9.2), 4.05 (br s, 1 H), 3.85 (dd, 1 H, J = 7.0, 15), 3.73 (dd,1 H, J = 7.3, 15), 3.20-3.29 (m, 1 H, 2.95-3.05 (m, 3 H), 2.43-2.51 (brs, 2 H), 1.20-2.10 (m, 14 H), 0.80-0.90 (m, 1 H), 0.72 (d, 3 H, J =6.7), 0.67 (d, 3 H, J = 6.7). 322 7 white 448.00 1.34 448.24 ¹H NMR(CDCl₃, 300 MHz) δ 7.73 solid min (d, 2 H, J = 8.7), 7.48 (d, 2 H, J =8.7), Method A 6.67 (s, 1 H), 5.43 (s, 1 H), 4.60 (d, 1 H, J = 5.1),4.45 (d, 1 H, J = 4.8), 4.15 (dd, 1 H, J = 5.6, 9.0), 3.25 (dd, 1 H, J =10, 15), 2.85-3.05 (m, 3 H), 2.70 (t, 1 H, J = 5.0), 2.67 (t, 1 H, J =4.7), 1.50-2.15 (m, 6 H), 1.10-1.40 (3 H), 0.75-0.90 (m, 1 H), 0.71 (d,3 H, J = 6.3), 0.66 (d, 3 H, J = 6.7). 323 9 tan 465.14 1.52 466.1 ¹HNMR (CDCl₃) δ 7.68 (d, 2 H, solid min J = 8.4 Hz), 7.46 (d, 2 H, J = 8.4Hz), Method B 7.43 (d, 2 H, J = 8.0 Hz), 7.10 (d, 2 H, J = 8.0 Hz), 6.19(s, br, 1 H), 5.16 (s, br, 1 H), 4.44 (dd, 2 H, J = 50 Hz, 15 Hz),4.31-4.35 (m, 1 H), 3.23 (s, 3 H), 1.85 (s, 3 H), 1.76-1.82 (m, 1 H),1.14-1.35 (m, 2 H), 0.78 (d, 3 H, J = 7.0 Hz), 0.65 (d, 3 H, J = 7.0Hz). 324 7 white 473.04 1.54 473.17 ¹H NMR (CDCl₃, 300 MHz) δ 7.73powder mins (d, 2 H, J = 8.1), 7.50 (d, 2 H, J = 8.1), Method A 6.67 (s,1 H), 5.85 (s, 1 H), 4.15 (dd, 1 H, J = 5.1, 9.2), 3.65 (d, 2 H, J =10), 3.26 (dd, 1 H, J = 9.9, 15), 2.97 (dd, 1 H, J = 4.4, 14), 2.60-2.85(m, 3 H), 2.80 (s, 6 H), 1.75-1.95 (m, 3 H), 1.05-1.30 (m, 3 H), 0.72(d, 3 H, J = 6.2), 0.65 (d, 3 H, J = 6.6). 325 7 white 507.06 1.41507.20 ¹H NMR (CDCl₃, 300 MHz) δ 8.64 solid min (s, 2 H), 7.72 (d, 3 H,J = 8.4), 7.50 (d, Method A 2 H, J = 8.8), 7.35 (dd, 1 H, J = 4.8, 7.7),6.63 (s, 1 H), 5.39 (br s, 1 H), 4.69 (br s, 1 H), 4.05-4.20 (m, 1 H),3.72 (br s, 1 H), 3.25 (m, 1 H), 2.50- 3.200 (m, 3 H), 1.50-2.10 (m, 5H), 1.00-1.40 (m, 3 H), 0.72 (d, 3 H, J = 6.6), 0.66 (d, 3 H, J = 6.6).326 1-Method A white 423.90 1.55 424.11 ¹H NMR (CDCl₃) δ 7.69-7.71 (m,solid min 3 H), 7.48-7.56 (m, 4 H), 6.11 (s, br, Method B 1 H), 5.22 (s,br, 1 H), 4.57 (dd, 2 H, J = 50 Hz, 15 Hz), 4.22-4.26 (m, 1 H),1.80-1.83 (m, 1 H), 0.99-1.23 (m, 3 H), 0.74 (t, 3 H, J = 8.0 Hz). 3271-Method A white 459.06 1.57 (M + Na)⁻ ¹H NMR (400 MHz, DMSO) δ 7.84solid min 481.9 (d, 2 H, J = 8.8), 7.80 (d, 2 H, J = 8.6), Method G 7.65(d, 2 H, J = 8.7), 7.59 (d, 2 H, J = 8.3, ), 7.47 (s, 1 H), 7.25 (s, 1H). 4.79 (ABq, 2 H, Δυ = 5.1, J_(ab) = 17.4), 4.43 (dd, 1 H, J = 8.5,6.6), 2.05 (m, 2 H), 1.82 (m, 1 H), 1.49 (m, 1 H). 328 1-Method A white502.06 1.83 (M − H)⁺ ¹H NMR (400 MHz, DMSO) δ 7.84 solid min 502.9 (d, 2H, J = 8.8), 7.68 (d, 2 H, J = 8.0), Method G 7.65-7.60 (m, 4 H), 7.47(s, 1 H), 7.26 (s, 1 H). 4.79 (s, 2 H), 4.45 (dd, 1 H, J = 8.8, 6.1),2.03 (m, 2 H), 1.82 (m, 1 H), 1.52 (m, 1 H). 329 1-Method A white 492.072.39 (M + H)⁺ ¹H NMR (400 MHz, DMSO) δ 7.91 solid min 492.9 (d, 2 H, J =8.3), 7.85 (d, 2 H, J = 8.8), Method G 7.64 (d, 2 H, J = 8.6), 7.54 (d,2 H, J = 8.3), 7.43 (s, 1 H), 7.23 (s, 1 H). 4.79 (ABq, 2 H, Δυ = 3.4,J_(ab) = 17.2), 4.42 (dd, 1 H, J = 8.5, 6.1), 3.85 (s, 3 H), 2.02 (m, 2H), 1.80 (m, 1 H), 1.52 (m, 1 H). 330 1-Method A white 473.08 1.60 (M +Na)⁺ ¹H NMR (400 MHz, DMSO) δ 7.83 solid Method G 495.9 (d, 2 H, J =8.8), 7.80 (d, 2 H, J = 8.3), 7.63 (d, 2 H, J = 8.6), 7.59 (d, 2 H, J =8.3), 7.50 (s, 1 H), 7.13 (s, 1 H). 4.83 (ABq, 2 H, Δυ = 36.2, J_(ab) =17.6), 4.37 (dd, 1 H, J = 8.5, 6.3), 2.09 (m, 1 H), 1.88 (m, 1 H), 1.64(m, 1 H), 1.45 (m, 1 H), 1.27 (m, 2 H). 331 1-Method A white 516.07 1.84(M + H)⁺ ¹H NMR (400 MHz, DMSO) δ 7.82 solid Method G 516.9 (d, 2 H, J =8.8), 7.69-7.60 (m, 6 H), 7.49 (s, 1 H), 7.13 (s, 1 H). 4.85 (ABq, 2 H,Δυ = 27.9, J_(ab) = 17.1), 4.38 (dd, 1 H, J = 9.0, 5.9), 2.05 (m, 1 H),1.75 (m, 1 H), 1.65 (m, 1 H), 1.46 (m, 1 H), 1.27 (m, 2 H). 332 1-MethodA white 506.09 1.67 (M + H)⁺ ¹H NMR (400 MHz, DMSO) δ 7.90 solid MethodG 506.9 (d, 2 H, J = 8.6), 7.83 (d, 2 H, J = 8.8), 7.62 (d, 2 H, J =8.8), 7.54 (d, 2 H, J = 8.3), 7.47 (s, 1 H), 7.11 (s, 1 H). 4.84 (ABq, 2H, Δυ = 36.1, J_(ab) = 17.4), 4.36 (dd, 1 H, J = 8.6, 6.1), 3.85 (s, 3H), 2.04 (m, 1 H), 1.82 (m, 1 H), 1.62 (m, 1 H), 1.45 (m, 1 H), 1.26 (m,2 H). 333 19 white 437.10 1.48 (M + Na)⁺ ¹H NMR (400 MHz, DMSO) δ 7.82solid Method G 459.9 (d, 2 H, J = 8.8), 7.79 (d, 2 H, J = 8.5), 7.63 (d,2 H, J = 8.8), 7.58 (d, 2 H, J = 8.3), 7.52 (s, 1 H), 7.09 (s, 1 H).4.82 (ABq, 2 H, Δυ = 37.2, J_(ab) = 17.6), 4.34 (dd, 1 H, J = 8.0, 6.6),4.25 (dt, 2 H, J_(d) = 47.2, J_(t) = 5.7), 1.58 (m, 1 H), 1.49-1.12 (m,5 H). 334 19 white 480.09 1.76 (M + Na)⁺ ¹H NMR (400 MHz, DMSO) δ 7.80solid Method G 502.9 (d, 2 H, J = 8.6), 7.67 (d, 2 H, J = 8.6), 7.60 (m,4 H), 7.52 (s, 1 H), 7.09 (s, 1 H), 4.83 (ABq, 2 H, Δυ = 30.1, J_(ab) =17.4), 4.36 (dd, 1 H, J = 8.6, 6.2), 4.22 (dt, 2 H, J_(d) = 47.5, J_(t)= 6.4), 1.61 (m, 1 H), 1.48-1.11 (m, 5 H). 335 19 white 470.11 1.58 (M +H)⁺ ¹H NMR (400 MHz, DMSO) δ 7.90 solid Method G 471.0 (d, 2 H, J =8.3), 7.82 (d, 2 H, J = 8.8), 7.62 (d, 2 H, J = 8.8), 7.53 (d, 2 H, J =8.4), 7.50 (s, 1 H), 7.07 (s, 1 H). 4.82 (ABq, 2 H, Δυ = 39.4, J_(ab) =17.4), 4.34 (dd, 1 H, J = 8.3, 6.6), 4.22 (dt, 2 H, J_(d) = 41.6, J_(t)= 6.1), 3.85 (s, 3 H), 1.58 (m, 1 H), 1.46-1.12 (m, 5 H). 336 19 white423.08 1.43 (M + H)⁺ ¹H NMR (400 MHz, DMSO) δ 7.82 solid Method G 423.9(d, 2 H, J = 8.8), 7.78 (d, 2 H, J = 8.3), 7.63 (d, 2 H, J = 6.8), 7.57(d, 2 H, J = 8.6), 7.53 (s, 1 H), 7.14 (s, 1 H), 4.81 (ABq, 2 H, Δυ =36.2, J_(ab) = 17.6), 4.38 (t, 1 H, J = 7.6), 4.27 (m, 1 H), 4.15 (m, 1H), 1.64 (m, 1 H), 1.54- 1.36 (m, 3 H). 337 19 white 466.07 1.72 (M +Na)⁺ ¹H NMR (400 MHz, DMSO) δ 7.80 solid Method G 489.0 (d, 2 H, J =8.8), 7.66 (d, 2 H, J = 8.1), 7.62-7.57 (m, 4 H), 7.54 (s, 1 H), 7.15(s, 1 H), 4.81 (ABq, 2 H, Δυ = 29.1, J_(ab) = 17.1), 4.40 (t, 1 H, J =6.9), 4.25 (m, 1 H), 4.13 (m, 1 H), 1.67 (m, 1 H), 1.55-1.39 (m, 3 H).338 19 yellow 456.09 1.54 (M + H)⁺ ¹H NMR (400 MHz, DMSO) δ 7.90 solidMethod G 457.0 (d, 2 H, J = 8.3), 7.83 (d, 2 H, J = 8.8), 7.62 (d, 2 H,J = 8.8), 7.52 (d, 2 H, J = 8.3), 7.50 (s, 1 H), 7.11 (s, 1 H), 4.82(ABq, 2 H, Δυ= 54.5, J_(ab) = 17.3), 4.37 (t, 1 H, J = 8.0), 4.28-4.03(m, 2 H), 3.85 (s, 3 H), 1.64 (m, 1 H), 1.53- 1.36 (m, 3 H). 339 19white 452.86 1.85 452.91 ¹H NMR (CDCl₃, 300 MHz) δ 7.70 solid min (d, 2H, J = 8.7), 7.54 (d, 2 H, J = 8.4), Method A 7.42-7.49 (m, 4 H), 6.31(br s, 1 H), 5.23 (br s, 1 H), 4.58-4.63 (m, 2 H), 4.33-4.41 (m, 2 H),4.19 (t, 1 H, J = 4.5), 2.18-2.37 (m, 1 H), 1.54-1.66 (m, 1 H). 340 19white 442.89 1.68 442.90 ¹H NMR (CDCl₃, 300 MHz) δ 7.96 solid min (d, 2H, J = 8.4), 7.72 (d, 2 H, J = 8.7), Method A 7.48 (d, 2 H, J = 8.7),7.39 (d, 2 H, J = 8.4), 6.32 (br s, 1 H), 5.18 (br s, 1 H), 4.54-4.63(m, 2 H), 4.30-4.42 (m, 2 H), 4.16 (t, 1 H, J = 4.5), 3.90 (s, 3 H),2.18-2.37 (m, 1 H), 1.54-1.66 (m, 1 H). 341 19 white 409.87 1.57 410.07¹H NMR (CDCl₃, 300 MHz) δ 7.72 solid min (dd, 2 H, J = 1.8, 8.7), 7.59(d, 2 H, J = Method A 8.1), 7.50 (dd, 2 H, J = 2.1, 8.7), 7.46 (d, 2 H,J = 8.1), 6.30 (br s, 1 H), 5.21 (br s, 1 H), 4.56-4.68 (m, 2 H),4.31-4.37 (m, 2 H), 4.18 (t, 1 H, J = 4.8), 2.17-2.37 (m, 1 H),1.48-1.64 (m, 1 H). 342 19 white 470.85 1.88 470.89 ¹H NMR (CDCl₃, 300MHz) δ 7.70 solid min (d, 2 H, J = 8.7), 7.56 (d, 2 H, J = 8.4), MethodA 7.51 (d, 2 H, J = 8.4), 7.43 (d, 2 H, J = 8.1), 6.32 (br s, 1 H), 5.75(tm, 1 H, J_(H-F) = 57), 5.34 (br s, 1 H), 4.52-4.63 (m, 2 H), 4.32 (d,1 H, J = 15.6), 2.51- 2.66 (m, 1 H), 1.54-1.69 (m, 1 H). 343 19 white460.88 1.74 461.07 ¹H NMR (CDCl₃, 300 MHz) δ 7.97 solid min (dd, 2 H, J= 2.0, 8.4), 7.72 (d, 2 H, J = Method A 8.7), 7.51 (d, 2 H, J = 8.7),7.38 (d, 2 H, J = 8.4), 6.32 (br s, 1 H), 5.75 (tm, 1 H, J_(H-F) = 57),5.18 (br s, 1 H), 4.60 (d, 1 H, J = 15.6), 4.50-4.55 (m, 1 H), 4.32 (d,1 H, J = 15.6), 3.91 (s, 3 H), 2.51-2.66 (m, 1 H), 1.54-1.69 (m, 1 H).344 19 white 427.85 1.62 428.06 ¹H NMR (CDCl₃, 300 MHz) δ 7.70 solid min(d, 2 H, J = 8.7), 7.61 (d, 2 H, J = 8.1), Method A 7.53 (d, 2 H, J =8.7), 7.45 (d, 2 H, J = 7.8), 6.32 (br s, 1 H), 5.71 (tm, 1 H, J_(H-F) =57), 5.21 (br s, 1 H), 4.64 (d, 1 H, J = 15.6), 4.51-4.55 (m, 1 H), 4.28(d, 1 H, J = 15.6), 2.48-2.60 (m, 1 H), 1.54-1.69 (m, 1 H). 345 1-Methodwhite 502.87 1.99 503.02 ¹H NMR (DMSO) δ 7.83 (d, 2 H, J = A, sep solidmin 8.8 Hz), 7.64 (m, 6 H), 7.46 (s br, cond 1 Method E 1 H), 7.25 (sbr, 1 H) 4.79 (s, 2 H), 4.44 (m, 1 H), 2.03 (m, 2 H), 1.83 (m, 1 H),1.50 (m, 1 H) 346 1-Method white 459.88 1.76 460.13 ¹H NMR (DMSO) δ 7.84(d, 2 H, A, sep solid min J = 8.0 Hz), 7.80 (d, 2 H, J = 7.7 Hz), cond 2Method E 7.65 (d, 2 H, J = 8.2 Hz), 7.59 (d, 2 H, J = 7.7 Hz), 7.47 (sbr, 1 H), 7.25 (s br, 1 H), 4.78 (AB₂, 2 H, Δυ = 5 Hz, J_(ab) = 17 Hz),4.43 (m, 1 H), 2.05 (m, 2 H), 1.83 (m, 1 H), 1.48 (m, 1 H) 347 1-Methodyellow 437.92 1.67 438.22 ¹H NMR (DMSO) δ 7.81 (m, 4 H), A, sep waxy min7.61 (m, 4 H), 7.53 (s br, 1 H), 7.09 cond 3 solid Method E (s br, 1 H),4.81 (AB₂, 2 H, Δυ = 5 Hz, J_(ab) = 17 Hz), 4.33 (m, 2 H), 4.19 (t, 1 H,J = 6.0 Hz), 1.44 (m, 6 H) 348 1-Method white 480.91 1.94 M + Na ¹H NMR(DMSO) δ 7.99 (d, 2 H, A, sep powder min 503.14 J = 8.8 Hz), 7.82 (m, 6H), 7.70 (s br, cond 3 Method E 1 H), 7.27 (s br, 1 H), 5.00 (m, 2 H),4.51 (m, 2 H), 4.33 (m, 1 H), 1.77 (m, 1 H), 1.47 (m, 6 H) 349 1-MethodA white 470.94 1.59 493.17 ¹H NMR (CDCl₃) δ 7.94 (d, powder min M + Na+J = 8.0 Hz, 2 H), 7.72 (d, J = 6.8 Hz, 2 H), Method B 7.46 (d, J = 6.8Hz, 2 H), 7.38 (d, J = 8.0, 2 H), 6.25 (s, br, 1 H), 5.26 (s, br, 1 H),4.37-4.62 (m, 3 H), 3.90 (s, 3 H), 2.45 (m, 1 H), 1.45 (m, 1 H), 1.27(d, J = 21.2 Hz, 3 H), 1.17 (d, J = 21.6 Hz, 3 H). 350 22 white 484.881.93 485.09 ¹H NMR (DMSO) δ 7.81 (d, 2 H, solid min J = 8.8 Hz), 7.63(m, 6 H), 7.51 (s br, Method E 1 H), 7.21 (s br, 1 H), 5.85 (t, 1 H, 56Hz), 4.81 (AB₂, 2 H, Δυ = 5 Hz, J_(ab) = 15 Hz), 4.42 (t, 1 H, J = 8.0Hz), 1.49 (m, 4 H) 351 1-Method A white 437.92 1.49 460.13 ¹H NMR(CDCl₃) δ 7.83 (d, solid min M + Na+ J = 6.8 Hz, 2 H), 7.58 (d, J = 8.4Hz, 2 H), Method B 7.48 (d, J = 8.4 Hz, 2 H), 7.45 (d, J = 6.8 Hz, 2 H),6.25 (s, br, 1 H), 5.28 (s, br, 1 H), 4.32-4.64 (m, 3 H), 2.45 (m, 1 H),1.38 (m, 1 H), 1.24 (d, J = 21.2 Hz, 3 H), 1.21 (d, J = 22 Hz, 3 H), 3521-Method A white 480.91 1.76 503.12 ¹H NMR (CDCl₃) δ 7.69 (d, solid minM + Na− J = 8.4 Hz, 2 H), 7.52 (d, J = 8.0 Hz, 2 H), Method B 7.45 (d, J= 8.4 Hz, 2 H), 7.43 (d, J = 8.0 Hz, 2 H), 6.30 (s, br, 1 H), 5.44 (s,br, 1 H), 4.34-4.66 (m, 3 H), 2.49 (m, 1 H), 1.46 (m, 1 H), 1.26 (d, J =21.6 Hz, 3 H), 1.22 (d, J = 21.6 Hz, 3 H), 353 18 white 466.89 1.41466.16 ¹H NMR (CDCl₃) δ 7.66 (d, 2 H, solid min J = 8.4 Hz) 7.45-7.55(m, 6 H), 6.17 (s, Method B br, 1 H), 5.19 (s, br, 1 H), 4.53 (dd, 2 H,J = 50 Hz, 15 Hz), 4.34-4.37 (m, 2 H), 4.22-4.25 (m, 1 H), 2.00-2.05 (m,1 H), 1.43-1.49 (m, 3 H). 354 18 white 423.90 1.54 424.1 ¹H NMR (d₆DMSO)δ 7.86 (d, 2 H, solid min J = 8.0 Hz) 7.48-7.75 (m, 6 H), 6.56 (s,Method B br, 1 H), 5.69 (s, br, 1 H), 4.72 (dd, 2 H, J = 42 Hz, 16 Hz),4.51-4.55 (m, 3 H), 1.43-2.07 (m, 4). 355 11 yellow 582.02 1.47 582.22¹H NMR (DMSO) δ 7.81 (d, 2 H, solid min J = 8.8 Hz), 7.63 (d, 2 H, J =8.5 Hz), Method E 7.43 (s br, 1 H), 7.24 (m, 4 H), 4.64 (s, 2 H), 4.42(m, 3 H), 3.99 (m, 2 H), 3.62 (m, 6 H), 3.23 (m, 2 H), 1.85 (m, 4 H) 35611 brown 595.06 1.42 595.23 ¹H NMR (DMSO) δ 7.80 (d, 2 H, solid min J =8.8 Hz), 7.63 (d, 2 H, J = 8.5 Hz), Method E 7.42 (s br, 1 H), 7.17 (m,4 H), 4.62 (s, 2 H), 4.41 (m, 1 H), 4.18 (m, 2 H), 3.96 (s, 1 H), 3.39(m, 2 H), 3.05 (m, 7 H), 2.78 (s, 3 H), 1.97 (m, 3 H), 1.58 (m, 1 H) 35721 white 437.10 1.50 (M + Na)⁺ ¹H NMR (400 MHz, DMSO) δ 7.83 solidMethod G 460.2 (d, 2 H, J = 8.5), 7.75 (d, 2 H, J = 8.3), 7.68 (s, 1 H),7.64 (d, 2 H, J = 8.6), 7.49 (d, 2 H, J = 8.1), 7.20 (s, 1 H), 4.67(ABq, 2 H, Δυ = 28.3, J_(ab) = 17.3), 4.54 (dd, 1 H, J = 9.3, 3.2), 2.23(m, 1 H), 1.42 (m, 1 H), 1.25 (d, 3 H, J = 21.6), 1.21 (d, 3 H, J =21.7). 358 21 white 480.09 1.76 (M + Na)⁺5 ¹H NMR (400 MHz, DMSO) δ 7.80solid Method G 03.2 (d, 2 H, J = 8.6), 7.69 (s, 1 H), 7.61 (m, 4 H),7.50 (d, 2 H, J = 8.1), 7.22 (s, 1 H), 4.68 (ABq, 2 H, Δυ = 2.7, J_(ab)= 17.1), 4.57 (dd, 1 H, J = 9.1, 3.0), 2.26 (m, 1 H), 1.47 (m, 1 H),1.24 (d, 3 H, J = 21.5), 1.22 (d, 3 H, J = 21.5). 359 21 white 470.111.62 (M + Na)⁺4 ¹H NMR (400 MHz, DMSO) δ 7.86 solid Method G 93.2 (d, 2H, J = 8.3), 7.83 (d, 2 H, J = 8.8), 7.63 (m, 3 H), 7.44 (d, 2 H, J =8.3), 7.18 (s, 1 H), 4.67 (ABq, 2 H, Δυ = 10.3, J_(ab) = 17.1), 4.53(dd, 1 H, J = 9.3, 2.9), 3.85 (s, 3 H), 2.22 (m, 1 H), 1.46 (m, 1 H),1.22 (d, 3 H, J = 21.5), 1.19 (d, 3 H, J = 21.6). 360 18 white 409.871.53 407.99 ¹H NMR (CDCl₃) δ 7.72 (d, 2 H, solid min (M − H⁻) J = 8.4Hz) 7.58 (d, 2 H, J = 8.4 Hz), 7.50 Method B (d, 2 H, J = 8.4 Hz), 7.45(d, 2 H, J = 8.4 Hz), 6.29 (s, br, 1 H), 5.21 (s, br, 1 H), 4.19-4.67(m, 5 H), 2.17-2.28 (m, 1 H), 1.49-1.61 (m, 1 H). 361 18 white 452.861.56 452.85 ¹H NMR (CDCl₃) δ 7.69 (d, 2 H, solid min J = 8.4 Hz) 7.56(d, 2 H, J = 8.4 Hz), 7.49 Method B (d, 2 H, J = 8.4 Hz), 7.43 (d, 2 H,J = 8.4 Hz), 6.31 (s, br, 1 H), 5.24 (s, br, 1 H), 4.19-4.62 (m, 5 H),2.16-2.30 (m, 1 H), 1.56-1.63 (m, 1 H). 362 18 white 456.93 1.86 457.16¹H NMR (CDCl₃, 300 MHz) δ 7.96 solid min (d, 2 H, J = 8.4), 7.69 (dd, 2H, J = Method B 1.8, 8.4), 7.47 (ddd, 2 H, J = 1.5, 2.1, 8.7), 7.42 (d,2 H, J = 8.4), 6.19 (br s, 1 H), 5.18 (br s, 1 H), 4.64 (d, 1 H, J =15.6), 4.42 (d, 1 H, J = 15.9), 4.30- 4.35 (m, 2 H), 4.18 (t, 1 H, J =3.6), 3.90 (s, 3 H), 1.89-2.08 (m, 1 H), 1.38-1.50 (m, 3 H). 363 18white 456.97 1.80 454.98 ¹H NMR (CDCl₃, 300 MHz) δ 7.64 solid min (neg.ion) (d, 2 H, J = 8.7), 7.42 (d, 2 H, J = 8.7), Method B 7.38 (d, 2 H, J= 8.4), 7.26 (d, 2 H, J = 8.4), 6.19 (br, 1 H), 5.28 (br s, 1 H), 4.51(d, 1 H, J = 15.6), 4.39 (d, 1 H, J = 15.3), 4.30-4.35 (m, 2 H), 4.18(t, 1 H, J = 3.6), 1.92-2.08 (m, 1 H), 1.55 (s, 6 H), 1.35-1.50 (m, 3H). 364 18 white 442.90 1.73 443.12 ¹H NMR (CDCl₃, 300 MHz) δ 7.81 solidmin (d, 2 H, J = 8.4), 7.59 (dd, 2 H, J = Method B 1.8, 8.4), 7.29-7.33(m, 4 H), 6.76 (br, 1 H), 5.80 (br s, 1 H), 4.62 (d, 1 H, J = 16.2),4.44 (d, 1 H, J = 16.2), 4.31 (t, 1 H, J = 6.9), 3.85-4.10 (m, 2 H),1.70-1.85 (m, 1 H), 1.30-1.48 (m, 3 H). 365 11, sep off- 585.02 1.47582.18 ¹H NMR (DMSO) δ 7.80 (m, 2 H), cond 4 white min 7.62 (m, 2 H),7.42 (m, 1 H), 7.18 solid Method E (m, 4 H), 4.62 (m, 3 H), 4.42 (m, 1H), 4.14 (m, 1 H), 4.00 (m, 3 H), 3.58 (m, 4 H), 2.93 (m, 1 H), 2.70 (m,2 H), 2.01 (m, 2 H), 1.85 (m, 1 H), 1.59 (m, 1 H) 366 11, sep yellow595.06 1.43 595.19 ¹H NMR (CDCl₃) δ 7.72 (d, 2 H, cond 4 solid min J =8.7 Hz), 7.52 (d, 2 H, J = 8.8 Hz), Method E 7.14 (m, 1 H), 7.01 (m, 1H), 6.87 (m, 1 H), 6.24 (s br, 1 H), 5.36 (m, 1 H), 4.51 (m, 1 H), 4.28(m, 4 H), 3.23 (m, 9 H), 2.77 (m, 3 H), 1.94 (m, 3 H), 1.40 (m, 1 H) 36711, sep white 595.06 1.42 595.20 ¹H NMR (DMSO) δ 7.80 (m, 2 H), cond 4solid min 7.62 (m, 2 H), 7.42 (s br, 1 H), 7.18 Method E (m, 4 H), 4.61(m, 2 H), 4.42 (m, 1 H), 4.14 (m, 2 H), 3.72 (m, 1 H), 3.57 (m, 1 H),3.32 (s, 3 H), 2.75 (m, 6 H), 2.27 (m, 2 H), 1.97 (m, 3 H), 1.60 (m, 1H) 368 11, sep dark 546.04 1.55 546.20 ¹H NMR (CDCl₃) δ 7.77 (d, 2 H,cond 4 yellow min J = 8.5 Hz), 7.61 (d, 2 H, J = 8.5 Hz), solid Method E7.53 (m, 1 H), 7.19 (m, 4 H), 4.67 (ABq, 2 H, Δυ = 35, J_(ab) = 16 Hz),4.30 (m, 6 H), 4.01 (m, 4 H), 3.48 (m, 4 H), 1.68 (m, 1 H), 1.49 (m, 4H) 369 11, sep orange- 559.08 1.29 559.22 ¹H NMR (DMSO) δ 7.77 (d, 2 H,cond 4 yellow min J = 8.3 Hz), 7.60 (d, 2 H, J = 8.3 Hz), solid Method E7.50 (s br, 1 H), 7.16 (m, 4 H), 4.65 (ABq, 2 H, Δυ = 20, J_(ab) = 16Hz), 4.33 (m, 2 H), 4.18 (m, 4 H), 3.17 (m, 7 H), 2.78 (s, 3 H), 1.67(m, 1 H), 1.50 (m, 5 H) 370 11, sep yellow 528.05 1.32 528.17 ¹H NMR(DMSO) δ 7.74 (d, 2 H, cond 4 solid min J = 8.3 Hz), 7.60 (d, 2 H, J =8.3 Hz), Method E 7.44 (s br, 1 H), 7.35 (d, 2 H, J = 8.5 Hz), 7.08 (sbr, 1 H), 6.95 (d, 2 H, J = 8.5 Hz), 4.68 (ABq, 2 H, Δυ = 24, J_(ab) =16 Hz), 3.77 (m, 13 H), 1.66 (m, 1 H), 1.45 (m, 5 H) 371 11, sep light-541.09 1.26 541.24 ¹H NMR (DMSO) δ 7.77 (d, 2 H, cond 4 orange min J =8.3 Hz), 7.59 (d, 2 H, J = 8.3 Hz), solid Method E 7.43 (s br, 1 H),7.31 (d, 2 H, J = 8.5 Hz), 7.08 (s br, 1 H), 6.87 (d, 2 H, J = 8.8 Hz),4.66 (ABq, 2 H, Δυ = 16, J_(ab) = 16 Hz), 4.22 (m, 5 H), 3.17 (m, 8 H),2.77 (m, 3 H), 1.65 (m, 1 H), 1.46 (m, 5 H) 372 18, 8  amber 511.05 1.09511.21 ¹H NMR, 400 Hz, (CDCl₃) δ 7.66 (d, glass min 2 H, J = 8.0 Hz),7.43 (d, 2 H, J = 8.0 Hz), Method A 7.26 (d, 2 H, J = 8.0 Hz), 7.21 (d,2 H, J = 8.0 Hz), 6.25 (s, br, 1 H), 5.45 (s, br, 1 H), 4.52 (d, 1 H,J_(ab) = 12.0 Hz), 4.38 (d, 1 H, J_(ab) = 12.0 Hz), 4.29 (m, 2 H), 4.18(t, 1 H, J = 6.0 Hz), 3.72 (m, 1 H), 3.47 (s, 2 H), 2.29 (s, 3 H), 2.0(m, 2 H), 1.83 (m, 2 H) 373 18, 8  amber 498.01 1.40 498.20 ¹H NMR, 400Hz, (CDCl₃) δ 7.66 (d, glass min 2 H, J = 8.0 Hz), 7.44 (d, 2 H, J = 8.0Hz), Method A 7.27 (d, 2 H, J = 8.0 Hz), 7.22 (d, 2 H, J = 8.0 Hz), 6.24(s, br, 1 H), 5.42 (s, br, 1 H), 4.52 (d, 1 H, J_(ab) = 12.0 Hz), 4.38(d, 1 H, J_(ab) = 12.0 Hz), 4.29 (m, 2 H), 4.18 (m, 1 H), 3.68 (t, 4 H,J = 4.0 Hz), 3.45 (s, 2 H), 2.40 (s, br, 4 H), 1.99 (m, 1 H), 1.45 (m, 3H) 374 18, 8  amber 529.08 1.17 529.22 ¹H NMR, 400 Hz, (CDCl₃) δ 7.68(d, glass min 2 H, J = 8.0 Hz), 7.46 (d, 2 H, J = 8.0 Hz), Method A 7.25(t, 1 H, J = 6.0 Hz), 7.05 (t, 1 H, J = 6.0 Hz), 6.28 (s, br, 1 H), 5.49(s, br, 1 H), 4.54 (d, 1 H, J_(ab) = 12.0 Hz), 4.33 (m, 2 H), 4.22 (m, 1H), 3.57 (s, 2 H), 2.32 (s, 3 H), 2.01 (m, 1 H), 1.44 (m, 2 H) 375 18,8  amber 516.00 1.10 516.17 ¹H NMR, 400 Hz, (CDCl₃) δ 7.68 (d, glass min2 H, J = 8.0 Hz), 7.45 (d, 2 H, J = 8.0 Hz), Method A 7.28 (t, 1 H, J =6.0 Hz), 7.06 (t, 2 H, J = 6.0 Hz), 6.24 (s, br, 1 H), 5.40 (s, br, 1H), 4.53 (d, 1 H, J_(ab) = 12.0 Hz), 4.36 (d, 1 H, J_(ab) = 12.0 Hz),4.34 (m, 2 H), 4.21 (m, 1 H), 3.69 (t, 4 H, J = 4.0 Hz), 3.53 (s, 2 H),2.44 (s, br, 3 H), 2.0 (m, 1 H), 1.45 (m, 2 H) 376 18 white 451.91 1.39451.90 ¹H NMR (CDCl₃) δ 8.55 (s, 1 H), solid min 8.09 (s, 1 H), 7.75 (d,2 H), J = 8.0 Hz) Method B 7.62 (d, 2 H, J = 8.4 Hz), 7.47-7.51 (m, 4H), 6.36 (s, br, 1 H), 5.28 (s, br, 1 H), 4.31-4.62 (m, 5 H), 2.16-2.30(m, 1 H), 1.56-1.66 (m, 1 H). 377 22 white 441.89 1.65 M + Na ¹H NMR(CDCl₃) δ 7.69 (d, 2 H, solid min 464.01 J = 8.3 Hz), 7.60 (d, 2 H, J =8.3 Hz), Method E 7.49 (m, 4 H), 6.18 (s br, 1 H), 5.67 (tt, 1 H, J = 56Hz, 4.0 Hz), 5.22 (s br, 1 H), 4.52 (AB₂, 2 H, Δυ = 16, J_(ab) = 100Hz), 4.34 (m, 1 H), 2.03 (m, 1 H), 1.68 (m, 1 H), 1.38 (m, 1 H), 0.86(m, 1 H) 378 18 white 450.92 1.52 450.91 ¹H NMR (CDCl₃) δ 7.91 (s, 1 H),solid min 7.71 (m, 3 H) 7.63 (d, 2 H, J = 8.4 Hz), Method B 7.50 (d, 2H, J = 8.4 Hz), 7.41 (d, 2 H, J = 8.4 Hz), 6.47 (s, 1 H), 6.34 (s, br, 1H), 5.18 (s, br, 1 H), 4.30-4.60 (m, 5 H), 2.14-2.29 (m, 1 H), 1.56-1.66(m, 1 H). 379 18 white 468.96 1.53 469.04 ¹H NMR (CDCl₃) δ 8.64 (s, 1H), solid min 7.98 (d, 2 H, J = 8.4 Hz), 7.75 (d, 2 H, Method B J = 8.4Hz), 7.45-7.50 (m, 4 H), 6.35 (s, br, 1 H), 5.20 (s, br, 1 H), 4.22-4.64(m, 5 H), 2.20-2.35 (m, 1 H), 1.54- 1.62 (m, 1 H). 380 18 white 464.951.54 464.99 ¹H NMR (CDCl₃) δ 8.54 (s, 1 H), solid min 8.10 (s, 1 H),7.73 (d, 2 H, J = 8.4 Hz), Method B 7.62 (d, 2 H, J = 8.4 Hz), 7.48-7.52(m, 5 H), 6.22 (s, br, 1 H), 5.18 (s, br, 1 H), 4.32-4.69 (m, 5 H),2.09-2.19 (m, 1 H), 1.44-1.61 (m, 3 H). 381 18 white 465.94 1.49 465.96¹H NMR (CDCl₃) δ 8.55 (s, 1 H), solid min 8.09 (s, 1 H), 7.73 (d, 2 H, J= 8.4 Hz), Method B 7.62 (d, 2 H, J = 8.4 Hz), 7.47-7.51 (m, 4 H), 6.36(s, br, 1 H), 5.28 (s, br, 1 H), 4.31-4.66 (m, 5 H), 2.10-2.39 (m, 1 H),1.56-1.66 (m, 3 H). 382 1-Method A white 501.92 1.53 502.1 ¹H NMR(CDCl₃) δ 8.56 (s, 1 H), solid min 8.10 (s, 1 H), 7.72 (d, 2 H, J = 8.4Hz), Method B 7.64 (d, 2 H, J = 8.4 Hz), 7.49-7.52 (m, 4 H), 6.23 (s,br, 1 H), 5.22 (s, br, 1 H), 4.32-4.64 (m, 3 H), 1.44-2.20 (m, 4 H). 3831-Method A white 500.93 1.66 501.13 ¹H NMR (CDCl₃) δ 7.91 (s, 1 H),solid min 7.41-7.78 (m, 9 H), 6.47 (s, 1 H), 6.23 Method B (s, br, 1 H),5.27 (s, br, 1 H), 4.30-4.59 (m, 3 H), 1.47-2.21 (m, 4 H). 384  18, 11beige 532.01 1.36 532.18 ¹H NMR (DMSO) δ 7.80 (d, 2 H, solid min J = 8.3Hz), 7.61 (d, 2 H, J = 8.3 Hz), Method E 7.56 (s br, 1 H), 7.23 (s br, 1H), 7.19 (m, 3 H), 4.64 (ABq, 2 H, Δυ = 16, J_(ab) = 16 Hz), 4.51 (t, 1H, J = 8.0 Hz), 4.42 (m, 2 H), 4.03 (m, 12 H), 2.02 (m, 1 H), 1.82 (m, 1H) 385  18, 11 pale orange 545.05 1.32 545.25 ¹H NMR (DMSO) δ 7.79 (d, 2H, solid min J = 8.3 Hz), 7.60 (d, 2 H, J = 8.3 Hz), Method E 7.54 (sbr, 1 H), 7.14 (m, 5 H), 4.62 (ABq, 2 H, Δυ = 8.0 Hz, J_(ab) = 16 Hz),4.51 (t, 1 H, J = 8.0 Hz), 4.24 (m, 5 H), 3.17 (m, 8 H), 2.78 (m, 3 H),2.02 (m, 1 H), 1.81 (m, 1 H) 386  18, 11 yellow 514.02 1.33 514.20 ¹HNMR (DMSO) δ 7.80 (d, 2 H, residue min J = 8.3 Hz), 7.61 (d, 2 H, J =8.3 Hz), Method E 7.48 (s br, 1 H), 7.33 (d, 2 H, J = 8.3 Hz), 7.15 (sbr, 1 H), 6.95 (d, 2 H, J = 8.3 Hz), 4.65 (ABq, 2 H, Δυ = 8.0 Hz, J_(ab)= 16 Hz), 3.86 (m, 15 H), 2.03 (m, 1 H), 1.79 (m, 1 H) 387  18, 11orange 527.06 1.28 527.20 ¹H NMR (DMSO) δ 7.79 (d, 2 H, solid min J =8.3 Hz), 7.60 (d, 2 H, J = 8.3 Hz), Method E 7.47 (s br, 1 H), 7.30 (d,2 H, J = 8.3 Hz), 7.15 (s br, 1 H), 6.89 (d, 2 H, J = 8.3 Hz), 4.63(ABq, 2 H, Δυ = 8.0 Hz), J_(ab) = 16 Hz), 4.48 (t, 1 H, J = 8.0 Hz),4.15 (m, 4 H), 3.24 (m, 10 H), 2.79 (m, 3 H), 2.03 (m, 1 H), 1.80 (m, 1H) 388  18, 11 tan 560.06 1.65 559.14 ¹H NMR (DMSO) δ 7.76 (d, 2 H,solid min J = 8.3 Hz), 7.59 (m, 3 H), 7.21 (s br, Method E 1 H), 7.08 (sbr, 1 H), 7.04 (m, 2 H), 4.53 (m, 5 H), 3.92 (m, 4 H), 3.45 (m, 6 H),2.25 (m, 1 H), 1.54 (m, 1 H), 1.25 (d, 3 H, J = 20 Hz), 1.22 (d, 3 H, J= 20 Hz) 389 18 yellow 478.91 1.55 491.04 ¹H NMR (CDCl₃) δ 7.94 (s, 1H), solid min (M⁻Na) 7.72-7.76 (m, 3 H), 7.65 (d, 2 H, Method B J = 8.4Hz) 7.52 (d, 2 H, J = 8.4 Hz), 7.40 (d, 2 H, J = 8.4 Hz), 6.46 (s, 1 H),6.30 (s, br, 1 H), 5.21 (s, br, 1 H), 4.27-4.57 (m, 3 H), 2.51-2.60 (m,1 H), 1.53- 1.65 (m, 2 H). 390 18 white 469.90 1.48 470.1 ¹H NMR (CDCl₃)δ 7.90 (s, 1 H), solid min 7.40-7.76 (m, 9 H), 6.50 (s, 1 H), 6.27Method B (s, br, 1 H), 5.22 (s, br, 1 H), 4.25-4.55 (m, 3 H), 2.49-2.58(m, 1 H), 1.51- 1.62 (m, 2 H). 391 18, 6  white 469.97 1.59 470.09 ¹HNMR (MeOD, 400 MHz) δ 7.77 solid min (ddd, 2 H, J = 2.0, 2.4, 8.8), 7.71(d, Method A 2 H, J = 8.4), 7.51 (ddd, 2 H, J = 2.0, 2.4, 8.8), 7.48 (d,2 H, J = 8.0), 4.80 (d, 1 H, J = 16.4), 4.72 (d, 1 H, J = 16.4), 4.47(t, 1 H, J = 7.2), 4.05-4.28 (m, 2 H), 3.38 (q, 2 H, J = 1.30-1.48 (m, 3H), 1.85 (m, 1 H), 1.30-1.48 (m, 3 H), 1.20 (t, 3 H, J = 7.2). 392 18,6  white 500.00 1.57 500.10 ¹H NMR (MeOD, 400 MHz) δ 7.72- solid min7.81 (m, 4 H), 7.48-7.52 (m, 4 H), Method A 4.80 (d, 1 H, J = 16.4),4.72 (d, 1 H), J = 16.4), 4.47 (t, 1 H, J = 7.2), 4.05- 4.28 (m, 2 H),3.54 (s, 3 H), 3.25-2.36 (m, 4 H), 1.70-1.85 (m, 1 H), 1.30- 1.48 (m, 3H). 393 18, 6  white 484.00 1.65 484.12 ¹H NMR (MeOD, 400 MHz) δ 7.79solid min (d, 2 H, J = 8.8), 7.50-7.54 (m, 4 H), Method A 7.29-7.33 (m,2 H), 4.79 (d, 1 H, J = 16.4), 4.72 (d, 1 H, J = 16.4), 4.47 (t, 1 H, J= 7.2), 4.05-4.28 (m, 2 H), 3.52-3.56 (m, 2 H), 3.03 and 2.94 (2 s, 3H), 1.70-1.85 (m, 1 H), 1.30-1.48 (m, 3 H), 1.15-1.25 (m, 3 H). 394 18,6  white 533.03 1.36 533.15 ¹H NMR (MeOD, 400 MHz) δ 8.48 solid min (d,1 H, J = 4.8), 7.76-7.82 (m, 5 H), Method A 7.50-7.53 (m, 4 H), 7.41 (d,1 H, J = 8.0), 7.28-7.30 (m, 1 H), 4.82 (d, 1 H, J = 16.0), 4.72 (d, 1H, J = 16.4), 4.67 (s, 2 H), 4.48 (t, 1 H, J = 7.2), 4.05- 4.28 (m, 2H), 1.70-1.85 (m, 1 H), 1.30-1.48 (m, 3 H). 395 18, 8  amber 501.98 1.17502.25 ¹H NMR, 400 Hz, (CDCl₃) δ 7.77 (d, glass min 2 H, J = 8.0 Hz),7.51 (d, 2 H, J = 8.0 Hz), Method A 7.42 (t, 1 H, J = 6.0 Hz), 7.26 (d,1 H, J = 6.0 Hz), 7.14 (d, 1 H, J = 6.0 Hz), 6.35 (s, br, 1 H), 6.07 (s,br, 1 H), 4.82 (d, 1 H, J_(ab) = 12.0 Hz), 4.35 (m, 1 H), 4.19 (m, 5 H),3.59 (s, br, 4 H), 3.48 (d, br, 1 H), 2.90 (d, br, 1 H), 2.20 (m, 1 H),1.50 (m, 1 H) 396 18, 8  amber 515.02 1.21 515.27 ¹H NMR, 400 Hz,(CDCl₃) δ 7.76 (d, glass min 2 H, J = 8.0 Hz), 7.50 (d, 2 H, J = 8.0Hz), Method A 7.32 (m, 1 H), 7.19 (d, 1 H, J = 8.0 Hz), 7.07 (d, 1 H, J= 8.0 Hz), 6.35 (s, br, 1 H), 5.67 (s, br, 1 H), 4.86 (d, 1 H, J_(ab) =12.0 Hz), 4.70 (s, 2 H), 4.56 (m, 2 H), 4.17 (m, 6 H), 2.80 (s, 3 H),2.22 (m, 1 H), 1.54 (m, 1 H) 397 18, 8  amber 483.98 1.21 483.98 ¹H NMR,400 Hz, (CDCl₃) δ 7.77 (d, glass min 2 H, J = 8.0 Hz), 7.51 (d, 2 H, J =8.0 Hz), Method A 7.41 (d, 2 H, J = 8.0 Hz), 7.31 (d, 2 H, J = 8.0 Hz),6.34 (s, br, 1 H), 6.05 (s, br, 1 H), 4.83 (d, 1 H, J_(ab) = 12.0 Hz),4.51 (m, 1 H), 4.20 (m, 4 H), 3.94 (m, 5 H), 3.51 (d, 1 H, J = 12.0 Hz),3.40 (d, 1 H, J = 12.0 Hz), 2.89 (t, 1 H, J = 6.0 Hz), 2.76 (t, 1 H, J =6.0 Hz), 2.20 (m, 1 H), 1.51 (m, 1 H) 398 18, 8  amber 497.03 1.16498.74 ¹H NMR, 400 Hz, (CDCl₃) δ 7.76 (d, glass min 2 H, J = 8.0 Hz),7.51 (d, 2 H, J = 8.0 Hz), Method A 7.37 (d, 2 H, J = 8.0 Hz), 7.27 (d,2 H, J = 8.0 Hz), 6.31 (s, br, 1 H), 5.80 (s, br, 1 H), 4.82 (d, 1 H,J_(ab) = 12.0 Hz), 4.55 (m, 2 H), 4.16 (m, 5 H), 3.82 (d, 1 H), 2.78 (s,3 H), 2.21 (m, 1 H), 1.52 (m, 1 H) 399  20, 11 colorless 573.11 1.63 ¹HNMR (DMSO) δ 7.76 (d, 2 H, residue min J = 8.3 Hz), 7.59 (m, 3 H), 7.20(s br, Method E 1 H), 7.08 (s br, 1 H), 7.03 (m, 2 H), 4.53 (m, 11 H),3.92 (m, 4 H), 3.45 (m, 3 H), 2.24 (m, 1 H), 1.54 (m, 1 H), 1.25 (d, 3H, J = 20 Hz), 1.22 (d, 3 H, J = 20 Hz) 400 11 light 564.03 1.51 564.19¹H NMR (DMSO) δ 7.81 (d, 2 H, yellow min J = 8.3 Hz), 7.63 (d, 2 H, J =8.3 Hz), solid Method E 7.36 (m, 3 H), 7.20 (s br, 1 H), 6.96 (d, 2 H, J= 8.0 Hz), 4.64 (s, 2 H), 4.37 (m, 3 H), 4.00 (m, 2 H), 3.61 (m, 6 H),3.21 (m, 2 H), 1.97 (m, 2 H), 1.82 (m, 1 H), 1.60 (m, 1 H) 401 11 pale577.07 1.47 577.20 ¹H NMR (DMSO) δ 7.80 (d, 2 H, orange min J = 8.0 Hz),7.62 (d, 2 H, J = 8.0 Hz), solid Method E 7.33 (m, 3 H), 7.20 (s br, 1H), 6.89 (d, 2 H, J = 8.0 Hz), 4.63 (s, 2 H), 4.39 (m, 1 H), 4.10 (m, 2H), 3.25 (m, 10 H), 2.77 (s, 3 H), 1.89 (m, 2 H), 1.81 (m, 1 H), 1.60(m, 1 H) 402  20, 11 pale 542.07 1.51 542.21 ¹H NMR (DMSO) δ 7.77 (d, 2H yellow min J = 8.0 Hz), 7.59 (d, 2 H, J = 8.0 Hz), residue Method E7.55 (s br, 1 H), 7.26 (d, 2 H, J = 8.0 Hz), 7.15 (s br, 1 H), 6.90 (d,2 H, J = 8.0 Hz), 4.52 (m, 2 H), 4.32 (m, 2 H), 4.00 (m, 2 H), 3.71 (m,2 H), 3.38 (m, 7 H), 2.23 (m, 1 H), 1.55 (m, 1 H), 2.23 (m, 1 H), 1.21(d, 3 H, J = 20 Hz) 403  20, 11 light 555.12 1.45 555.27 ¹H NMR (DMSO) δ7.76 (d, 2 H orange min J = 8.0), 7.58 (d, 2 H, J = 8.0 Hz), solidMethod E 7.54 (s br, 1 H), 7.22 (d, 2 H, J = 8.0 Hz), 7.16 (s br, 1 H),6.84 (d, 2 H, J = 8.0 Hz), 4.52 (m, 2 H), 4.13 (m, 2 H), 3.25 (m, 11 H),2.79 (m, 3 H), 2.20 (m, 1 H), 1.56 (m, 1 H), 1.23 (d, 3 H, J = 20 Hz),1.20 (d, 3 H, J = 20 Hz) 404  18, 11 pale 532.01 1.43 532.18 ¹H NMR(DMSO) δ 7.81 (d, 2 H yellow min J = 8.0 Hz), 7.62 (d, 2 H, J = 8.0 Hz),residue Method E 7.48 (s br, 1 H), 7.34 (d, 2 H, J = 8.0 Hz), 7.25 (sbr, 1 H), 6.96 (d, 2 H, J = 8.0 Hz), 5.72 (tt, 1 H, J = 8.0 Hz, 56 Hz),4.61 (s, 2 H), 4.52 (t, 1 H, J = 8.0 Hz), 4.33 (t, 2 H, J = 8.0 Hz),3.96 (m, 2 H), 3.56 (m, 2 H), 3.22 (m, 2 H), 2.24 (m, 1 H), 1.95 (m, 1H) 405  18, 11 pale 545.05 1.37 545.19 ¹H NMR (DMSO) δ 7.81 (d, 2 Hyellow min J = 8.0 Hz), 7.61 (d, 2 H, J = 8.0 Hz), solid Method E 7.46(s br, 1 H), 7.30 (d, 2 H, J = 8.0 Hz), 7.25 (s br, 1 H), 6.89 (d, 2 H,J = 8.0 Hz), 5.64 (m, 1 H), 4.60 (s, 2 H), 4.52 (t, 1 H, J = 8.0 Hz),4.11 (m, 2 H), 3.17 (m, 10 H), 2.77 (m, 3 H), 2.24 (m, 1 H), 1.96 (m, 1H) 406  18, 11 yellow 550.00 1.43 550.16 ¹H NMR (DMSO) δ 7.80 (d, 2 Hresidue min J = 8.0 Hz), 7.62 (d, 2 H, J = 8.0 Hz), Method E 7.56 (s,br, 1 H), 7.23 (m, 4 H), 5.80 (tt, 1 H, J = 4.0 Hz, 56 Hz), 3.93 (m, 15H), 2.29 (m, 1 H), 1.99 (m, 1 H) 407  18, 11 orange 563.04 1.37 563.21¹H NMR (DMSO) δ 7.80 (d, 2 H solid min J = 8.0 Hz), 7.62 (d, 2 H, J =8.0 Hz), Method E 7.55 (s br, 1 H), 7.29 (s br, 1 H), 7.15 (m, 3 H),5.78 (tt, 1 H, J = 4.0 Hz, 56 Hz), 4.56 (m, 3 H), 4.21 (m, 2 H), 3.2 (m,10 H), 2.79 (m, 3 H), 2.30 (m, 1 H), 1.97 (m, 1 H) 408 18,  clear 442.94 0.993 443.19 ¹H NMR (CDCl₃) δ 8.07 (s, 1 H), 10,  oil min 7.67 (d, J =6.8 Hz, 2 H), 7.55 (d, sep Method B J = 8.8 Hz, 1 H), 7.44 (d, J = 6.8Hz, cond 5 2 H), 6.47 (d, J = 8.8 Hz, 1 H), 6.30 (s, br, 1 H), 5.45 (s,br, 1 H), 4.20-4.46 (m, 5 H), 3.12 (s, 6 H), 1.22-1.85 (m, 4 H). 40918,  clear 442.94  0.993 443.19 ¹H NMR (CDCl₃) δ 8.07 (s, 1 H), 10,  oilmin 7.67 (d, J = 6.8 Hz, 2 H), 7.55 (d, sep Method B J = 8.8 Hz, 1 H),7.44 (d, J = 6.8 Hz, cond 5 2 H), 6.47 (d, J = 8.8 Hz, 1 H), 6.30 (s,br, 1 H), 5.45 (s, br, 1 H), 4.20-4.46 (m, 5 H), 3.12 (s, 6 H),1.22-1.85 (m, 4 H). 410 20, 8  amber 512.04 1.44 512.20 ¹H NMR, 400 Hz,(CDCl₃) δ 7.69 (d, glass min 2 H, J = 8.0 Hz), 7.42 (d, 2 H, J = 8.0Hz), Method B 7.22 (dd, 4 H, J = 8.0 Hz), 6.27 (s, br, 1 H), 5.26 (s,br, 1 H), 4.58 (d, 1 H), 4.43 (d, 1 H, J_(ab) = 16 Hz), 4.36 (d, 1 H,J_(ab) = 16.0 Hz), 3.68 (m, 6 H), 3.46 (s, 2 H), 2.45 (m, 6 H), 1.53 (m,1 H), 1.26 (d, 3 H, J = 20.0 Hz), 1.17 (d, 3 H, J = 20.0 Hz) 411 20, 8 amber 525.08 1.38 525.24 ¹H NMR, 400 Hz, (CDCl₃) δ 7.69 (d, glass min 2H, J = 8.0 Hz), 7.42 (d, 2 H, J = 8.0 Hz), Method B 7.22 (dd, 4 H, J =8.0 Hz), 6.26 (s, br, 1 H), 5.24 (s, br, 1 H), 4.57 (m, 1 H), 4.43 (d, 1H, J_(ab) = 16.0 Hz), 4.35 (d, 1 H, J_(ab) = 16.0 Hz), 3.48 (s, 2 H),2.47 (m, 7 H), 2.30 (s, 3 H), 1.26 (d, 3 H, J = 22.0 Hz), 1.18 (d, 3 H,J = 22.0 Hz) 412 18 white 427.87 1.39 428.13 ¹H NMR (CDCl₃, 400 MHz) δ7.72 solid min (dd, 2 H, J = 2.0, 8.8), 7.61 (d, 2 H, J = Method B 8.4),7.53 (dd, 2 H, J = 2.0, 8.4), 7.45 (d, 2 H, J = 8.0), 6.32 (br s, 1 H),5.73 (tm, 1 H, J_(H-F) = 57), 5.22 (br s, 1 H), 4.64 (d, 1 H, J = 16.4),4.50-4.60 (m, 1 H), 4.28 (d, 1 H, J = 16.4), 2.42-2.60 (m, 1 H),1.50-1.63 (m, 1 H). 413 18 white 470.86 1.69 471.13 ¹H NMR (CDCl₃, 400MHz) δ 7.69 solid min (dd, 2 H, J = 1.6, 8.8), 7.56 (d, 2 H, J = MethodB 8.4), 7.51 (ddd, 2 H, J = 2.0, 2.4, 8.4), 7.43 (d, 2 H, J = 8.4), 6.32(br s, 1 H), 5.75 (tm, 1 H, J_(H-F) = 57), 5.25 (br s, 1 H), 4.60 (d, 1H, J = 15.6), 4.50- 4.60 (m, 1 H), 4.32 (d, 1 H, J = 15.6), 2.50-2.60(m, 1 H), 1.55-1.70 (m, 1 H). 414  18, 13 white 480.95 1.41 481.22 ¹HNMR (CDCl₃, 400 MHz) δ 7.96 solid min (d, 2 H, J = 8.4), 7.70 (d, 2 H, J= 8.4), Method B 7.47-7.50 (m, 4 H), 6.22 (br s, 1 H), 5.18 (br s, 1 H),4.66 (d, 1 H, J = 15.6), 4.43 (d, 1 H, J = 15.6), 4.30- 4.35 (m, 2 H),4.19-4.21 (m, 1 H), 2.61 (s, 3 H), 1.93-2.08 (m, 1 H), 1.38-1.50 (m, 3H). 415  18, 10 white 428.92 1.34 429.18 ¹H NMR (CDCl₃) TFA salt δ 8.10(s, foam Method B 1 H), 8.04 (d, 1 H, J = 9.2 Hz), 7.76 (d, 2 H, J = 6.8Hz), 7.52 (d, 2 H, J = 6.8 Hz), 6.80 (d, 2 H, J = 9.2 Hz), 6.46 (s, 1H), 6.00 (s, 1 H), 4.60 (d, 1 H, J = 15.6 Hz), 4.54 (dd, 1 H, J = 5.2Hz, 6.2 Hz), 4.30 (m, 1 H), 4.18 (m, 1 H), 4.07 (d, 1 H, J = 15.6 Hz),3.29 (s, 6 H), 2.25 (m, 1 H), 1.55 (m, 1 H). 416 1-Method A off-white463.91 1.50 464.11 ¹H NMR (CDCl₃, 300 MHz) δ 8.72 solid min (d, 1 H, J =2.4), 7.82 (dd, 1 H, J = Method B 2.7, 8.4), 7.55 (d, 2 H, J = 8.1),7.47 (d, 2 H, J = 8.1), 7.37 (d, 1 H, J = 8.4), 5.97 (br s, 1 H), 5.26(br s, 1 H), 4.62 (d, 1 H, J = 16.2), 4.54 (d, 1 H, J = 15.9), 4.44 (t,1 H, J = 7.5), 1.70-1.77 (m, 1 H), 1.35-1.43 (m, 1 H), 1.21- 1.31 (m, 1H), 0.85 (d, 3 H, J = 6.3), 0.67 (d, 3 H, J = 6.6). 417 1-Method A white453.95 1.37 454.14 ¹H NMR (CDCl₃, 300 MHz) δ 8.71 solid min (d, 1 H, J =3.0), 7.96 (d, 2 H, J = 8.1), Method B 7.85 (dd, 1 H, J = 2.4, 8.4),7.37-7.43 (m, 3 H), 5.99 (br s, 1 H), 5.24 (br s, 1 H), 4.61 (d, 1 H, J= 15.9), 4.53 (d, 1 H, J = 15.9), 4.41 (t, 1 H, J = 7.2), 3.91 (s, 3 H),1.70-1.76 (m, 1 H), 1.35-1.43 (m, 1 H), 1.21-1.31 (m, 1 H), 0.82 (d, 3H, J = 6.6), 0.66 (d, 3 H, J = 6.6). 418 1-Method A white 420.92 1.64421.15 ¹H NMR (CDCl₃, 300 MHz) δ 8.74 solid min (d, 1 H, J = 2.4), 7.90(dd, 1 H, J = Method A 2.4, 8.4), 7.61 (d, 2 H, J = 8.4), 7.50 (d, 2 H,J = 8.4), 7.44 (d, 1 H, J = 8.4), 5.92 (br s, 1 H), 5.22 (br s, 1 H),4.65 (d, 1 H, J = 16.5), 4.52 (d, 1 H, J = 16.5), 4.40 (t, 1 H, J =7.5), 1.65-1.74 (m, 1 H), 1.33-1.40 (m, 1 H), 1.18- 1.25 (m, 1 H), 0.83(d, 3 H, J = 6.6), 0.66 (d, 3 H, J = 6.6). 419 7 white 528.12 1.35528.26 ¹H NMR (CDCl₃, 500 MHz) δ 7.72 solid min (d, 2 H, J = 8.6), 7.51(d, 2 H, J = 8.8), Method A 6.65 (s, 1 H), 5.35 (s, 1 H), 4.14 (dd, 1 H,J = 5.1, 9.5), 3.63-3.75 (m, 2 H), 3.35-3.55 (m, 3 H), 3.25 (dd, 1 H, J= 9.8, 14), 2.98 (dd, 1 H, J = 4.5, 14), 2.35-2.87 (m, 8 H), 1.77-1.92(m, 3 H), 1.59 (d, 2 H, J = 13), 1.05-1.30 (m, 3 H), 0.75-0.80 (m, 1 H),0.72 (d, 3 H, J = 6.4), 0.67 (d, 3 H, J = 6.7). 420 7 white 515.08 1.56515.33 ¹H NMR (CDCl₃, 500 MHz) δ 7.71 solid min (d, 2 H, J = 8.5), 7.50(d, 2 H, J = 8.5), Method A 6.65 (s, 1 H), 5.47 (s, 1 H), 4.13 (dd, 1 H,J = 5.2, 9.2), 3.60-3.75 (m, 6 H), 3.15-3.30 (m, 6 H), 2.97 (dd, 1 H, J= 4.6, 14), 2.71 (dd, 2 H, J = 14, 25), 1.75-1.92 (m, 3 H), 1.67 (d, 1H, J = 12), 1.05-1.30 (m, 3 H), 0.75-0.81 (m, 1 H), 0.71 (d, 3 H, J =6.7), 0.65 (d, 3 H, J = 6.7). 421 7 white 460.00 1.68 460.17 ¹H NMR(CDCl₃, 500 MHz) δ 7.73 solid min (d, 2 H, J = 8.5), 7.50 (d, 2 H, J =8.6), Method A 6.65 (s, 1 H), 5.35 (s, 1 H), 4.15 (dd, 3 H, J = 5.2,9.5), 3.67 (s, 3 H), 3.25 (t, 1 H, J = 10), 3.97 (dd, 1 H, J = 4.8, 14),2.61-2.80 (m, 2 H), 1.74-1.94 (m, 3 H), 0.89-1.40 (m, 4 H), 0.75-0.80(m, 1 H), 0.72 (d, 3 H, J = 6.4), 0.67 (m, 3 H, J = 6.7). 422 1-Method Atan 491.81 1.84 491.04 ¹H NMR (CDCl₃) δ 7.71 (2, 2 H, solid min J = 8.0Hz), 7.50-7.58 (m, 2 H), 7.41 (d, Method B 2 H, J = 8.0 Hz), 7.17-7.22(m, 1 H), 6.23 (s, br, 1 H), 5.25 (s, br, 1 H), 4.41 (dd, 2 H, J = 50Hz, 15 Hz), 4.31-4.35 (m, 1 H), 1.80-1.86 (m, 1 H), 1.41- 1.44 (m, 1 H),1.11-1.15 (m, 1 H), 0.81 (d, 3 H, J = 7.0 Hz), 0.71 (d, 3 H, J = 7.0Hz). 423 1-Method A white 424.09 1.54 (M − H)⁺ ¹H NMR (400 MHz, DMSO) δ7.90 solid min 425.1 (d, 2 H, J = 8.1), 7.82 (d, 2 H, J = 8.5), Method F7.61 (d, 2 H, J = 8.5), 7.52 (d, 2 H, J = 8.1), 7.49 (s, 1 H), 7.07 (s,1 H), 4.81 (ABq, 2 H, Δυ = 45.3, J_(ab) = 17.3), 4.27 (t, 1 H, J = 7.3),3.85 (s, 3 H), 1.55 (m, 1 H), 1.38 (m, 1 H), 0.68 (t, 3 H, J = 7.3). 4241-Method A white 452.12 1.69 (M + H)⁻ ¹H NMR (400 MHz, DMSO) δ 7.90solid min 453.1 (d, 2 H, J = 8.3), 7.83 (d, 2 H, J = 8.8), Method F 7.62(d, 2 H, J = 8.8), 7.54 (d, 2 H, J = 8.3), 7.48 (s, 1 H), 7.04 (s, 1 H),4.82 (ABq, 2 H, Δυ = 41.3, J_(ab) = 17.3), 4.31 (t, 1 H, J = 8.1), 3.85(s, 3 H), 1.52 (m, 1 H), 1.29 (m, 1 H), 1.04 (m, 3 H), 0.90 (m, 1 H),0.63 (t, 3 H, J = 7.3). 425 1-Method A pale 460.99 1.48 460.13 ¹H NMR(CDCl₃, 300 MHz) δ 7.91 yellow min (d, 1 H, J = 1.5), 7.67-7.72 (m, 3H), solid Method B 7.62 (d, 2 H, J = 8.7), 7.42-7.48 (m, 4 H), 6.46 (t,1 H, J = 2.1), 6.24 (br s, 1 H), 5.21 (br s, 1 H), 4.62 (d, 1 H, J =15.3), 4.42 (d, 1 H, J = 15.6), 4.29 (t, 1 H, J = 6.9), 1.80-1.88 (m, 1H), 1.28-1.40 (m, 1 H), 1.12-1.21 (m, 1 H), 0.75 (d, 3 H, J = 6.6), 0.66(d, 3 H, J = 6.6). 426 1-Method A white 461.97 1.39 462.18 ¹H NMR(CDCl₃, 300 MHz) δ 8.54 solid min (s, 1 H), 8.10 (s, 1 H), 7.71 (d, 2 H,J = Method B 8.4), 7.61 (d, 2 H, J = 8.4), 7.46-7.52 (m, 4 H), 6.23 (brs, 1 H), 5.19 (br s, 1 H), 4.66 (d, 1 H, J = 15.9), 4.42 (d, 1 H, J =15.9), 4.30 (t, 1 H, J = 6.9), 1.79-1.89 (m, 1 H), 1.30-1.38 (m, 1 H),1.07-1.14 (m, 1 H), 0.76 (d, 3 H, J = 6.6), 0.66 (d, 3 H, J = 6.6). 42711 pale 542.07 1.48 542.25 ¹H NMR (CDCl₃) δ 7.71 (d, 2 H, yellow min J =8.00 Hz), 7.49 (d, 2 H, J = 8.0 Hz), solid Method E 7.16 (d, 1 H, J =12.0 Hz), 7.05 (d, 1 H, J = 8.0 Hz), 6.86 (t, 1 H, J = 8.0 Hz), 6.40 (s,br, 1 H), 5.87 (s br, 1 H), 4.42 (ABq, 2 H, Δυ = 16, J_(ab) = 164 Hz),4.49 (d, 2 H, J = 4.0 Hz), 4.27 (t, 1 H, J = 8.0 Hz), 4.04 (m, 4 H),3.69 (m, 2 H), 3.51 (m, 2 H), 3.10 (m, 2 H), 1.83 (m, 1 H), 1.29 (m, 1H), 1.07 (m, 1 H), 0.75 (d, 3 H, J = 8.0 Hz), 0.68 (d, 3 H, J = 8.0 Hz).428 11 yellow 555.12 1.41 555.28 ¹H NMR (CDCl₃) δ 7.71 (d, 2 H, solidmin J = 8.00 Hz), 7.50 (d, 2 H, J = 8.0 Hz), Method E 7.16 (d, 1 H, J =12.0 Hz), 7.05 (d, 1 H, J = 8.0 Hz), 6.87 (t, 1 H, J = 8.0 Hz), 6.38 (s,br, 1 H), 5.91 (s br, 1 H), 4.41 (AB₂, 2 H, Δυ = 16, J_(ab) = 176 Hz),4.45 (m, 2 H), 4.27 (t, 1 H, J = 8.0 Hz), 3.81 (m, 4 H), 3.67 (m, 4 H),3.48 (m, 1 H), 2.89 (s, 3 H), 1.83 (m, 1 H), 1.29 (m, 1 H), 1.05 (m, 1H), 0.75 (d, 3 H, J = 8.0 Hz), 0.68 (d, 3 H, J = 8.0 Hz). 429 7 white545.17 1.84 545.36 ¹H NMR (CDCl₃, 500 MHz) δ 7.73 solid min (d, 2 H, J =9.0), 7.51 (d, 2 H, J = 8.0), Method C 6.65 (2 s, 1 H), 5.40 (s, 1 H),4.54 (t, 1 H, J = 13), 3.85-4.20 (m, 2 H), 2.40- 3.50 (m, 12 H),1.75-2.00 (m, 3 H), 0.92-1.20 (m, 1 H), 0.73 (d, 3 H, J = 5.8, 6.1),0.67 (d, 3 H, J = 6.1, 6.4). 430 7 white 541.16 1.43 541.24 ¹H NMR(CDCl₃, 500 MHz) δ 7.71 solid min (d, 2 H, J = 6.4), 7.50 (d, 2 H, J =8.2), Method A 6.65 (d, 1 H, J = 41), 5.44 (s, 1 H), 4.55 (t, 1 H, J =13), 4.15 (br s, 1 H), 3.95 (br s, 1 H), 3.15-3.35 (m, 1 H), 2.90-3.00(m, 2 H), 2.60-2.70 (m, 2 H), 2.50-2.57 (m, 2 H), 2.35-2.50 (m, 6 H),1.85-2.00 (m, 3 H), 1.35- 1.75 (m, 3 H), 1.00-1.30 (m, 5 H), 0.90-1.00(m, 1 H), 0.72 (dd, 3 H, J = 7.0, 7.3), 0.66 (dd, 3 H, J = 6.1, 6.4).431 7 white 529.10 1.38 529.27 ¹H NMR (CDCl₃, 500 MHz) δ 7.72 solid min(d, 2 H, 8.5), 7.51 (d, 2 H, J = 8.9), Method A 6.65 (d, 1 H, J = 32),5.43 (s, 1 H), 4.55 (t, 1 H, J = 13) 4.14 (dd, 1 H, J = 4.8, 9.5), 3.88(br s, 4 H), 3.21-3.84 (m, 2 H), 2.90-3.05 (m, 3 H), 2.47- 2.67 (m, 1H), 1.80-2.05 (m, 3 H), 1.40-1.75 (m, 6 H), 1.00-1.35 (m, 4 H), 0.73(dd, 3 H, J = 3.4, 6.4), 0.67 (dd, 3 H, J = 2.7, 6.7). 432 7 white474.02 1.55 474.28 ¹H NMR (CDCl₃, 500 MHz) δ 7.72 (d, solid min 2 H, J =7.6), 7.50 (d, 2 H, J = 8.6), Method A 6.65 (d, 1 H, J = 40), 5.46 (s, 1H), 4.56 (t, 1 H, J = 13), 4.00-4.20 (m, 2 H), 3.80-3.90 (m, 1 H), 3.40(s, 3 H), 3.20-3.35 (m, 1 H), 2.85-3.05 (m, 2 H), 2.40-2.65 (m, 1 H),1.50-2.00 (m, 5 H), 1.00-1.45 (m, 2 H), 0.83- 0.90 (m, 1 H), 0.72 (dd, 3H, J = 6.7, 8.2), 0.67 (dd, 3 H, J = 5.8, 6.4). 433 1-Method A white455.00 1.83 454.15 ¹H NMR (CDCl₃, 300 MHz) δ 7.61 solid min (dd, 2 H, J= 1.8, 8.7), 7.40 (ddd, 2 H, Method B J = 2.1, 2.4, 8.7), 7.26 (d, 4 H,J = 7.2), 6.25 (br s, 1 H), 5.19 (br s, 1 H), 4.51 (d, 1 H, J = 15.6),4.43 (d, 1 H, J = 15.6), 4.34 (t, 1 H, J = 7.2), 1.75- 1.85 (m, 1 H),1.69 (s, 3 H), 1.62 (s, 3 H), 1.22-1.35 (m, 2 H), 0.78 (d, 3 H, J =6.3), 0.66 (d, 3 H, J = 6.3). 434 7 white 542.15 1.73 542.46 ¹H NMR(CDCl₃, 500 MHz) δ 7.72 solid min (d, 2 H, J = 8.5), 7.51 (d, 2 H, J =8.5), Method C 6.65 (d, 1 H, J = 39), 5.42 (s, 1 H), 4.55 (t, 1 H, J =14), 4.00-4.17 (m, 2 H), 3.05-3.33 (m, 3 H), 2.85-3.05 (m, 2 H),2.40-2.70 (m, 8 H), 2.32 (s, 3 H), 1.55-2.10 (m, 6 H), 1.00-1.30 (m, 6H), 0.72 (t, 3 H, J = 6.7, 6.7), 0.67 (t, 3 H, J = 6.1, 6.4). 435 7white 497.02 1.70 479.19 ¹H NMR (CDCl₃, 500 MHz) δ 8.31 solid min (s, 1H), 7.76 (d, 2 H, J = 8.9), 7.56 (d, Method A 2 H, J = 8.5), 6.74 (s, 1H), 4.81 (t, 1 H, J = 7.6), 4.71 (br s, 1 H), 4.20 (br s, 1 H), 3.13 (t,2 H, J = 8.6), 2.70- 2.95 (m, 2 H), 2.05-2.20 (m, 1 H), 1.85-2.00 (m, 2H), 1.55-1.85 (m, 4 H), 1.10-1.35 (m, 3 H), 1.00 (d, 3 H, J = 6.4), 0.97(d, 3 H, J = 6.7), 0.87 (t, 1 H, J = 7.0). 436 13 white 476.99 1.76477.22 ¹H NMR (CDCl₃, 300 MHz) δ 7.94 solid min (dd, 2 H, J = 1.8, 8.4),7.69 (dd, 2 H, J = Method B 1.8, 8.7), 7.45-7.50 (m, 4 H), 6.23 (br s, 1H), 5.19 (br s, 1 H), 4.65 (d, 1 H, J = 15.9), 4.46 (d, 1 H, J = 15.9),4.31 (dd, 1 H, J = 6.6, 7.8), 2.61 (s, 3 H), 1.75-1.85 (m, 1 H),1.28-1.35 (m, 1 H), 1.08-1.15 (m, 1 H), 0.76 (d, 3 H, J = 6.6), 0.64 (d,3 H, J = 6.6). 437 14 pale 476.99 1.92 477.18 ¹H NMR (CDCl₃, 300 MHz) δ7.94 yellow min (d, 2 H, J = 8.4), 7.70 (dd, 2 H, J = solid Method B1.8, 8.4), 7.45-7.52 (m, 4 H), 6.23 (br s, 1 H), 5.19 (br s, 1 H), 4.67(d, 1 H, J = 16.2), 4.47 (d, 1 H, J = 15.9), 4.31 (t, 1 H, J = 7.2),2.47 (s, 3 H), 1.75- 1.85 (m, 1 H), 1.28-1.35 (m, 1 H), 1.08-1.15 (m, 1H), 0.76 (d, 3 H, J = 6.6), 0.64 (d, 3 H, J = 6.6). 438 6 white 480.031.81 480.26 ¹H NMR (CDCl₃, 300 MHz) δ 7.67 solid min (d, 2 H, J = 8.7),7.45 (d, 2 H, J = 8.7), Method B 7.38 (d, 2 H, J = 8.1), 7.32 (d, 2 H, J= 7.5), 6.23 (br s, 1 H), 5.19 (br s, 1 H), 4.59 (d, 1 H, J = 16.2),4.45 (d, 1 H, J = 15.9), 4.30 (t, 1 H, J = 6.9), 3.47- 3.56 (br m, 1 H),3.15-3.35 (br m, 1 H), 2.81-3.09 (br m, 3 H), 1.75-1.85 (m, 1 H),1.05-1.40 (m, 5 H), 0.76 (d, 3 H, J = 6.6), 0.65 (d, 3 H, J = 6.6). 4396 white 529.06 1.60 529.25 ¹H NMR (CDCl₃, 300 MHz) δ 8.57 solid min (d,1 H, J = 4.8), 7.80 (d, 2 H, J = 8.4), Method B 7.70-7.73 (m, 2 H), 7.67(d, 2 H, J = 8.4), 7.45 (d, 2 H, J = 8.4), 7.42 (d, 2 H, J = 7.8), 7.36(d, 1 H, J = 7.8), 7.28 (br s, 1 H), 6.23 (br s, 1 H), 5.22 (br s, 1 H),4.77 (d, 2 H, J = 4.8), 4.63 (d, 1 H, J = 15.9), 4.44 (d, 1 H, J =15.9), 4.29 (t, 1 H, J = 7.2), 1.73-1.85 (m, 1 H), 1.25-1.38 (m, 1 H),1.06- 1.14 (m, 1 H), 0.75 (d, 3 H, J = 6.3), 0.65 (d, 3 H, J = 6.6). 4408 amber 512.04 1.36 512.24 ¹H NMR 400 Hz (CDCl₃) δ 7.70 (d, glass min 2H, J = 8.0 Hz), 7.74 (d, 2 H, Method A J = 8.0 Hz), 7.31 (d, 2 H, J = 6Hz), 7.08 (d, 2 H, J = 8.0 Hz), 6.25 (s, br, 1 H), 5.41 (s, br, 1 H),4.56 (d, 1 H, J_(ab) = 12 Hz), 4.43 (d, 1 H, J_(ab) = 12 Hz), 4.35 (t, 1H, J = 6.0 Hz), 3.72 (t, 4 H, J = 4.0 Hz), 3.56 (s, 2 H), 2.48 (t, 4 H,J = 41.0 Hz), 1.79 (m, 1 H), 1.36 (m, 1 H), 1.18 (m, 1 H), 0.79 (d, 3 H,J = 6.0 Hz), 0.69 (d, 3 H, J = 6.0 Hz) 441 8 amber 525.08 1.35 525.23 ¹HNMR 400 Hz (CDCl₃) δ 7.69 (d, glass min 2 H, J = 8.0 Hz), 7.47 (d, 2 H,Method A J = 8.0 Hz), 7.28 (t, 1 H, J = 6.0 Hz), 7.07 (dd, 2 H, J = 8.0Hz), 6.29 (s, br, 1 H), 5.55 (s, br, 1 H), 4.46 (d, 1 H, J_(ab) = 14.0Hz), 4.41 (d, 1 H, J_(ab) = 14.0 Hz), 4.34 (t, 1 H, J = 6.0 Hz), 3.58(s, 2 H), 2.33 (s, 3 H), 1.78 (m, 1 H), 1.18 (m, 1 H), 0.79 (d, 3 H, J =6.0 Hz), 0.68 (d, 3 H, J = 6.0 Hz) 442 1-Method A amber 470.94 1.74471.12 ¹H NMR 400 Hz (CDCl₃) δ 7.78 (t, glass min 1 H, J = 6.0 Hz), 7.72(d, 2 H, Method A J = 8.0 Hz), 7.51 (d, 2 H, J = 8.0 Hz), 7.19 (m, 2 H),6.21 (s, br, 1 H), 5.37 (s, br, 1 H), 4.64 (d, 1 H, J_(ab) = 14.0 Hz),4.47 (d, 1 H, J_(ab) = 14.0 Hz), 4.34 (t, 1 H, J = 6.0 Hz), 3.95 (s, 3H), 1.80 (m, 1 H), 1.37 (m, 1 H), 1.01 (m, 1 H), 0.80 (d, 3 H, J = 6.0Hz), 0.69 (d, 3 H, J = 6.0 Hz) 443 21 white 435.10 1.40 (M + Na)⁺ ¹H NMR(400 MHz, DMSO) δ 7.84 solid min 458.2 (d, 2 H, J = 8.6), 7.76 (d, 2 H,J = 8.3), Method D 7.62 (d, 2 H, J = 8.8), 7.51 (d, 2 H, J = 8.3), 7.40(s, 1 H), 7.11 (s, 1 H), 4.63 (ABq, 2 H, Δυ = 5.9, J_(ab) = 17.6), 4.56(dd, 1 H, J = 8.3, 2.5), 4.54 (s, 1 H), 1.95 (dd, 1 H, J = 13.7, 8.6),1.26 (dd, 1 H, J = 13.6, 2.4), 1.04 (s, 3 H), 0.99 (s, 3 H). 444 7 clearoil 465.17 1.38 466.20 ¹H NMR (CDCl₃, 500 MHz) δ 7.73 min (d, 2 H, J =8.8), 7.50 (d, 2 H, J = 8.9), Method A 6.67 (s, 1 H), 5.37 (s, 1 H),4.14 (dd, 1 H, J = 5.5, 9.5), 3.25 (dd, 1 H, J = 10, 14), 2.97 (dd, 1 H,J = 4.5, 14), 2.87-2.95 (m, 2 H), 2.65-2.75 (m, 2 H), 2.07-2.23 (m, 2H), 1.83-1.90 (m, 1 H), 1.50-1.82 (m, 4 H), 1.15- 1.40 (m, 3 H),0.77-0.85 (m, 1 H), 0.72 (d, 3 H, J = 6.7), 0.66 (d, 3 H, J = 6.4). 4456 amber 456.92 1.62 457.32 ¹H NMR 400 Hz (CDCl₃) δ 7.77 (d, glass min 2H, J = 6.0 Hz), 7.68 (t, 1 H, J = 6.0 Hz), Method A 7.64 (d, 2 H, J =8.0 Hz), 7.39 (m, 3 H), 6.21 (s, br, 1 H), 5.35 (s, br, 1 H), 4.67 (d, 1H, J_(ab) = 14.0 Hz), 4.38 (d, 1 H, J_(ab) = 14.0 Hz), 3.44 (m, 1 H),1.88 (m, 1 H), 1.59 (m, 2 H), 0.79 (d, 3 H, J = 6.0 Hz), 0.69 (d, 3 H, J= 6.0 Hz) 446 18 off-white 417.09 1.53 (M + Na)⁺ ¹H NMR (400 MHz, DMSO)δ 7.82 solid min 418.2 (d, 2 H, J = 8.8), 7.74 (d, 2 H, J = 8.5), MethodF 7.63 (d, 2 H, J = 8.8), 7.62 (s, 1 H), 7.53 (d, 2 H, J = 8.5), 7.09(s, 1 H), 4.80 (ABq, 2 H, Δυ = 17.9, J_(ab) = 17.8), 4.70 (s, 1 H), 4.62(t, 1 H, J = 7.6), 4.60 (s, 1 H), 2.34 (dd, 1 H, J = 14.4, 7.1), 2.02(dd, 1 H, J = 14.6, 7.3), 1.57 (s, 3 H). 447 18 off-white 458.12 1.59(M + Na)⁺ ¹H NMR (400 MHz, DMSO) δ 8.45 solid min 459.2 (d, 1 H, J =2.2), .82 (d, 2 H, J = 8.6), Method G 7.72 (m, 3 H), 7.60 (d, 2 H, J =8.8), 7.57 (s, 1 H), 7.44 (d, 2 H, J = 8.5), 7.09 (s, 1 H), 6.54 (t, 1H, J = 2.0), 4.74 (ABq, 2 H, Δυ = 25.5, J_(ab) = 16.8), 4.71 (s, 1 H),4.61 (m, 2 H), 2.37 (dd, 1 H, J = 14.2, 7.1), 2.08 (dd, 1 H, J = 14.7,7.6), 1.57 (s, 3 H). 448 18 off-white 442.90 1.74 443.05 ¹H NMR (CDCl₃,400 MHz) δ 7.96 solid min (d, 2 H, J = 8.2), 7.72 (d, 2 H, J = 8.0),Method A 7.48 (d, 2 H, J = 8.0), 7.39 (d, 2 H, J = 8.0), 6.33 (br s, 1H), 5.20 (br s, 1 H), 4.55-4.62 (m, 2 H), 4.39 (d, 1 H, J = 15.4),4.28-4.32 (m, 1 H), 4.17-4.21 (m, 1 H), 3.90 (s, 3 H), 2.17-2.35 (m, 1H), 1.56-1.65 (m, 1 H). 449  18, 12 yellow 442.94 1.65 442.11 ¹H NMR(CDCl₃, 400 MHz) δ 7.67 foam min (ddd, 2 H, J = 2.0, 2.6, 8.8), 7.42Method A (ddd, 2 H, J = 2.0, 2.3, 8.8), 7.39 (d, 2 H, J = 8.2), 7.24 (d,2 H, J = 8.2), 6.34 (br s, 1 H), 5.35 (br s, 1 H), 4.56 (dd, 1 H, J =5.8, 8.5), 4.48 (d, 1 H, J = 15.5), 4.35 (d, 1 H, J = 15.5), 4.30- 4.33(m, 1 H), 4.18-4.22 (m, 1 H), 2.23-2.39 (m, 1 H), 1.56-1.670 (m, 2 H),1.57 (s, 6 H). 450  18, 13 white 466.92 1.61 467.18 ¹H NMR (CDCl₃, 400MHz) δ 7.96 solid min (ddd, 2 H, J = 1.7, 2.0, 8.4), 7.73 Method A (ddd,2 H, J = 1.9, 2.5, 8.7), 7.49 (ddd, 2 H, J = 2.0, 2.3, 8.7), 7.46 (d, 2H, J = 8.6), 6.34 (br s, 1 H), 5.21 (br s, 1 H), 4.64 (d, 1 H, J =15.4), 4.57- 4.60 (m, 1 H), 4.39 (d, 1 H, J = 16.1), 4.30-4.32 (m, 1 H),4.18-4.21 (m, 1 H), 2.61 (s, 3 H), 2.18-2.36 (m, 1 H), 1.55-1.66 (m, 1H). 451 18, 7  clear oil 533.07 1.71 533.02 ¹H NMR (CDCl₃, 400 MHz) δ7.73 min (d, 2 H, J = 8.6), 7.51 (d, 2 H, J = 8.8), Method A 6.67 (s, 1H), 5.51 (s, 1 H), 4.14-4.52 (m, 4 H), 3.76-3.95 (m, 2 H), 3.50- 3.72(m, 1 H), 3.19-3.27 (m, 1 H), 2.86-3.07 (m, 1 H), 2.56-2.80 (m, 2 H),1.70-1.99 (m, 7 H), 1.36-1.63 (m, 10 H). 452 18, 7  clear oil 517.072.53 517.32 ¹H NMR (CDCl₃, 400 MHz) δ 7.74 (d, min 2 H, J = 8.6), 7.50(d, 2 H, J = 8.5), Method A 6.70 (s, 1 H), 5.60 (s, 1 H), 4.50 (dd, 1 H,J = 4.9, 9.8), 4.22-4.31 (m, 2 H), 3.81-4.00 (m, 5 H), 3.53-3.66 (m, 2H), 3.40-3.50 (m, 1 H), 3.13-3.25 (m, 3 H), 2.89 (dd, 1 H, J = 4.6, 14),2.62-2.77 (m, 3 H), 1.50-1.95 (m, 6 H), 1.01-1.45 (m, 5 H). 453 18, 7 clear oil 531.09 2.27 531.36 ¹H NMR (CDCl₃, 400 MHz) δ 7.73 min (d, 2 H,J = 8.6), 7.51 (d, 2 H, J = 8.6), Method A 6.65 (d, 1 H, J = 28), 5.47(s, 1 H), 4.50-4.63 (m, 1 H), 4.20-4.45 (m, 1 H), 4.05-4.15 (m, 2 H),3.55-3.65 (m, 2 H), 3.05-3.35 (m, 6 H), 2.85- 3.00 (m, 3 H), 2.55-2.35(m, 2 H), 1.50-2.00 (m, 6 H), 1.00-1.45 (m, 7 H). 454 8 amber 533.991.40 534.27 ¹H NMR (CDCl₃) δ 7.78 (d, glass min 2 H, J = 8.0 Hz), 7.39(m, 6 H), 6.34 (s, Method A br, 1 H), 5.80 (s, br, 1 H), 4.72 (d, 1 H,J_(ab) = 14.0 Hz), 4.16 (m, 1 H), 4.34 (d, 1 H, J_(ab) = 14.0 Hz), 3.60(m, 4 H), 3.84 (s, 2 H), 2.62 (m, 2 H), 2.25 (m, 4 H) 455 18, 8  amber501.98 1.27 502.24 ¹H NMR 400 Hz (CDCl₃) δ 7.79 (d, glass min 2 H, J =8.0 Hz); 7.39 (m, 6 H), 6.33 (s, Method A br, 1 H), 5.80 (s, br, 1 H),4.68 (d, 1 H, J_(ab) = 14.0 Hz), 4.22 (d, 1 H, J_(ab) = 14.0 Hz), 3.55(s, 2 H), 2.62 (m, 2 H), 2.43 (m, 8 H), 2.30 (s, 3 H) 456 18, 8  amber515.02 1.22 515.31 ¹H NMR 400 Hz (CDCl₃) δ 7.79 (d, glass min 2 H, J =8.0 Hz), 7.52 (d, 2 H, Method A J = 8.0 Hz), 7.39 (m, 4 H), 6.34 (s, br,1 H), 5.78 (s, br, 1 H), 5.72 (t, 1 H, J = 54.0 Hz), 4.68 (d, 1 H,J_(ab) = 14.0 Hz), 4.34 (d, 1 H, J_(ab) = 14.0 Hz), 3.88 (m, 1 H), 3.56(m, 4 H), 2.49 (m, 2 H), 2.26 (m, 4 H) 457 8 amber 547.03 1.26 547.20 ¹HNMR 400 Hz (CDCl₃) δ 7.78 (d, glass min 2 H, J = 8.0 Hz), 7.50 (d, 2 H,Method A J = 8.0 Hz), 7.41 (m, 4 H), 6.35 (s, br, 1 H), 5.80 (s, br, 1H), 5.72 (t, 1 H, J = 54.0 Hz), 4.68 (d, 1 H, J_(ab) = 14.0 Hz), 4.35(d, 1 H, J_(ab) = 14.0 Hz), 3.87 (m, 1 H), 3.55 (s, 2 H), 2.44 (m, 10H), 2.30 (s, 3 H) 458 18,  white 446.91 1.01 447.13 ¹H NMR (CDCl₃) TFAsalt δ 8.14 (s, 1-Method B foam Method B 1 H), 7.98 (d, 1 H, J = 9.6Hz), 7.76 (d, 2 H, J = 6.8 Hz), 7.55 (d, 2 H, J = 6.8 Hz), 6.81 (d, 2 H,J = 9.6 Hz), 6.45 (s, 1 H), 6.10 (s, 1 H), 5.70 (t, 1 H, J = 110.0 Hz),4.60 (d, 1 H, J = 16.0 Hz), 4.51 (m, 1 H), 4.06 (d, 1 H, J = 16 Hz),3.30 (s, 6 H), 2.55 (m, 1 H), 1.60 (m, 1 H). 459 18,  white 456.97 1.14457.23 ¹H NMR (CDCl₃) TFA salt δ 8.11 (s, 1-Method B foam Method B 1 H),7.95 (d, 1 H, J = 9.6 Hz), 7.77 (d, 2 H, J = 6.8 Hz), 7.51 (d, 2 H, J =6.8 Hz), 6.76 (d, 2 H, J = 9.6 Hz), 6.34 (s, 1 H), 6.02 (s, 1 H), 4.58(d br., 1 H, J = 8.4 Hz), 4.46 (d, 1 H, J = 16.0 Hz), 4.06 (d, 1 H, J =16 Hz), 3.29 (s, 6 H), 2.50 (m, 1 H), 1.39 (m, 1 H), 1.25 (d, 3 H, J =22.0 Hz), 1.17 (d, 3 H, J = 22.0 Hz). 460 1-Method B light 478.92 1.89479.21 ¹H NMR (CDCl₃) δ 8.09 (s, 1 H), 8.01 yellow min (d, 1 H, J = 9.2Hz), 7.75 (d, 2 H, gummy 3 × 50 J = 8.4 Hz), 7.53 (d, 2 H, J = 8.4 Hz),mm 6.82 (d, 1 H, J = 9.2 Hz), 6.62 (s, br, ODS-AC- 1 H), 6.12 (s, br, 1H), 4.18-4.58 (m, 18 3 H), 3.30 (s, 6 H), 2.15 (m, 1 H), column, 2.05(m, 1 H), 1.85 (m, 1 H), 1.40 (m, 4 mL/min, 1 H) 0-100% MeOH/ H2O 0.1%TFA 4 min gradient 461 18 clear 438.28 1.41 438.01 ¹H NMR (CDCl₃) δ 8.33(s, 1 H), 7.73 oil min (d, 1 H, J = 8.4 Hz), 7.71 (d, 2 H, Method B J =8.8 Hz), 7.51 (d, 2 H, J = 8.8 Hz), 7.27 (d, 1 H, J = 8.4 Hz), 6.56 (s,br, 1 H), 6.11 (s, br, 1 H), 5.69 (m, 1 H), 4.21-4.62 (m, 3 H), 2.52 (m,1 H), 1.63 (m, 1 H) 462 1 white 470.30 1.53 470.02 ¹H NMR (CDCl₃) δ 8.38(s, 1 H), solid min 7.79 (d, 1 H, J = 8.0 Hz), 7.68 (d, 2 H, Method B J= 8.4 Hz), 7.50 (d, 2 H, J = 8.4 Hz), 7.31 (d, 1 H, J = 8.0 Hz), 6.57(s, br, 1 H), 6.25 (s, br, 1 H), 4.29-4.64 (m, 3 H), 2.12 (m, 1 H), 1.98(m, 1 H), 1.81 (m, 1 H), 1.43 (m, 1 H) 463 18 clear 434.32 1.43 434.13¹H NMR (CDCl₃) δ 8.37 (s, 1 H) oil min 7.70 (d, 1 H, J = 8.8 Hz), 7.68(d, 1 H, Method B J = 8.8 Hz), 7.67 (d, 2 H, J = 6.8 Hz), 7.48 (d, 2 H,J = 6.8 Hz), 6.25 (s, br, 1 H), 5.31 (s, br, 1 H), 4.34-4.62 (m, 5 H),1.35-2.05 (m, 4 H) 464 18, 7  clear 469.14 1.14 470.17 ¹H NMR (CDCl₃,400 MHz) δ 7.73 oil min (d, 2 H, J = 8.8), 7.51 (d, 2 H, J = 8.8),Method A 6.65 (s, 1 H), 5.39 (s, 1 H), 4.05-4.35 (m, 2 H), 3.25 (dd, 1H, J = 10, 14), 2.85-3.04 (m, 3 H), 2.65-2.85 (m, 2 H), 2.09-2.29 (m, 2H), 1.93-2.10 (m, 1 H), 1.83-1.91 (m, 10 H). 465 15 white 476.99 1.91477.13 ¹H NMR (CDCl₃, 500 MHz) δ 7.98 solid min (d, 2 H, J = 8.2), 7.68(d, 2 H, J = 8.9), Method A 7.45 (d, 4 H, J = 8.5), 6.21 (s, 1 H), 5.19(s, 1 H), 4.62 (d, 1 H, J = 15), 4.48 (d, 1 H, J = 16), 4.31 (t, 1 H, J= 7.0), 2.65 (s, 3 H), 1.75-1.85 (m, 1 H), 1.20-1.35 (m, 4 H), 1.10-1.17(m, 1 H), 0.85-0.90 (m, 1 H), 0.75 (d, 3 H, J = 6.7), 0.64 (d, 3 H, J =6.4). 466 1-Method B clear 520.96 1.17 521.19 ¹H NMR (CDCl₃) δ 8.16 (s,1 H), gummy min 8.06 (d, 1 H, J = 9.2 Hz), 7.75 (d, 2 H, solid Method BJ = 8.4 Hz), 7.50 (d, 2 H, J = 8.4 Hz), 7.31 (d, 1 H, J = 9.2 Hz), 6.67(s, br, 1 H), 6.20 (s, br, 1 H), 4.19-4.60 (m, 3 H), 3.87 (m, 4 H), 3.69(m, 4 H), 2.14 (m, 1 H), 1.98 (m, 1 H), 1.83 (m, 1 H), 1.38 (m, 1 H) 46718,  clear 470.95  0.983 471.19 ¹H NMR (CDCl₃) δ 8.15 (s, 1 H), 1-MethodB gummy min 8.10 (d, 1 H, J = 9.2 Hz), 7.77 (d, 2 H, solid Method B J =8.4 Hz), 7.53 (d, 2 H, J = 8.4 Hz), 6.93 (d, 1 H, J = 9.2 Hz), 6.65 (s,br, 1 H), 6.22 (s, br, 1 H), 4.09-4.67 (m, 5 H), 3.87 (m, 4 H), 3.68 (m,4 H), 2.25 (m, 1 H), 1.63 (m, 1 H) 468 1-Method B clear 499.01  1.153499.23 ¹H NMR (CDCl₃) δ 8.12 (s, 1 H), gummy min 8.07 (d, 1 H, J = 9.2Hz), 7.78 (d, 2 H, solid Method B J = 8.4 Hz), 7.52 (d, 2 H, J = 8.4Hz), 6.91 (d, 1 H, J = 9.2 Hz), 6.63 (s, br, 1 H), 6.19 (s, br, 1 H),4.07-4.62 (m, 3 H), 3.86 (m, 4 H), 3.68 (m, 4 H), 2.46 (m, 1 H), 1.31(m, 1 H), 1.25 (d, 3 H, J = 21.6), 1.17 (d, 3 H, J = 21.6) 469 15 white511.43 1.90 511.13 ¹H NMR (CDCl₃, 400 MHz) δ 8.01 solid min (d, 2 H, J =8.3), 7.69 (d, 2 H, J = 8.8), Method C 7.43-7.51 (m, 4 H), 6.20 (s, 1H), 5.15 (s, 1 H), 4.74 (s, 2 H), 4.63 (d, 1 H, J = 15), 4.47 (d, 1 H, J= 16), 4.31 (t, 1 H, J = 6.8), 1.74-1.87 (m, 1 H), 1.04- 1.88 (m, 4 H),0.82-0.94 (m, 1 H), 0.76 (d, 3 H, J = 6.6), 0.65 (d, 3 H, J = 6.6). 4701 white 529.11 2.17 529.11 ¹H NMR (CDCl₃, 400 MHz) δ 7.95 solid min (d,2 H, J = 8.4), 7.71 (dd, 2 H, J = Method D 1.6, 8.4), 7.48 (dd, 2 H, J =2.4, 8.8), 7.38 (dd, 2 H, J = 2.4, 8.8), 6.31 (br s, 1 H), 5.22 (br s, 1H), 4.60 (d, 1 H, J = 15.6), 4.55-4.58 (m, 1 H), 4.38-4.42 (m, 3 H),4.29-4.32 (m, 1 H), 4.17- 4.21 (m, 1 H), 2.18-2.32 (m, 2 H), 1.12 (dd, 2H, J = 6.8, 8.4), 0.08 (s, 9 H). 471  15, 13 white 510.14 1.86 511.13 ¹HNMR (CDCl₃, 400 MHz) δ 8.01 solid min (d, 2 H, J = 8.4), 7.69 (d, 2 H, J= 8.8), Method A 7.47 (d, 2 H, J = 8.0), 7.46 (d, 2 H, J = 8.8), 6.20(br s, 1 H), 5.20 (br s, 1 H), 4.74 (s, 2 H), 4.64 (d, 1 H, J = 15),4.49 (d, 1 H, J = 15), 4.31 (t, 1 H, J = 7.0), 1.73-1.87 (m, 1 H),1.20-1.37 (m, 1 H), 1.07-1.17 (m, 1 H), 0.76 (d, 3 H, J = 6.6), 0.65 (d,3 H, 6.6). 472 15, 8  white 519.17 1.42 520.18 ¹H NMR (CDCl₃, 400 MHz) δ8.02 solid min (d, 2 H, J = 7.6), 7.71 (d, 2 H, J = 8.4), Method A 7.52(d, 2 H, J = 8.0), 7.48 (d, 2 H, J = 8.4), 6.23 (br s, 1 H), 5.17 (br s,1 H), 4.70 (d, 1 H, J = 16), 4.44 (d, 1 H, J = 16), 4.31 (t, 1 H, J =6.4), 3.70 (s, 2 H), 3.02 (s, 6 H), 1.75-1.90 (m, 1 H), 1.00-1.40 (m, 2H), 0.76 (d, 3 H, J = 6.8), 0.66 (d, 3 H, J = 6.4). 473 1 off-white460.89 2.11 461.08 ¹H NMR (CDCl₃, 300 MHz) δ 7.97 foam min (d, 2 H, J =8.4), 7.72 (d, 2 H, J = 8.4), Method A 7.51 (dd, 2 H, J = 2.0, 8.4),7.38 (d, 2 H, J = 8.0), 6.32 (br s, 1 H), 5.71 (tm, 1 H, J_(H-F) = 55),5.19 (br s, 1 H), 4.60 (d, 1 H, J = 15.6), 4.49-4.53 (m 1 H), 4.33 (d, 1H, J = 15.6), 3.91 (s, 3 H), 2.42-2.68 (m, 1 H), 1.54-1.65 (m, 1 H). 4741 pale 462.92 2.24 485.07 ¹H NMR (CDCl₃, 400 MHz) δ 7.67 yellow min (M +Na⁺) (d, 2 H, J = 8.4), 7.47 (d, 2 H, J = 8.8), foam Method A 7.25-7.29(m, 4 H), 6.33 (br s, 1 H), 5.72 (tm, 1 H, J_(H-F) = 57), 5.23 (br s, 1H), 4.49-4.53 (m, 1 H), 4.46 (d, 1 H, J = 15.6), 4.34 (d, 1 H, J =15.0), 2.52-2.60 (m, 1 H), 1.55-1.65 (m, 1 H), 1.68 (s, 3 H), 1.63 (s, 3H). 475   1, 13 white foam 484.91 1.67 485.07 ¹H NMR (CDCl₃, 400 MHz) δ7.97 min (d, 2 H, J = 8.0), 7.73 (dd, 2 H, J = Method D 2.0, 8.8), 7.52(dd, 2 H, J = 2.0, 8.8), 7.45 (d, 2 H, J = 8.4), 6.34 (br s, 1 H), 5.73(tm, 1 H, J_(H-F) = 57), 5.20 (br s, 1 H), 4.63 (d, 1 H, J = 15.6),4.52-4.55 (m, 1 H), 4.32 (d, 1 H, J = 15.6), 2.61 (s, 3 H), 2.55-2.60(m, 1 H), 1.61-1.65 (m, 1 H). 476   1, 12 white foam 460.93 1.72 483.07¹H NMR (CDCl₃, 400 MHz) δ 7.68 min (M + Na⁺) (dd, 2 H, J = 2.0, 8.8),7.48 (dd, 2 H, J = Method D 8.4), 7.41 (d, 2 H, J = 8.4), 7.23 (d, 2 H,J = 8.8), 6.30 (br s, 1 H), 5.73 (tm, 1 H, J_(H-F) = 57), 5.18 (br s, 1H), 4.48-4.52 (m, 1 H), 4.44 (d, 1 H, J = 15.2), 4.34 (d, 1 H, J =15.2), 2.50- 2.65 (m, 1 H), 1.61-1.70 (m, 1 H), 1.56 (s, 6 H). 477 7clear oil 455.93 0.99 456.20 ¹H NMR (CDCl₃, 400 MHz) δ 7.72 min 7.86 (m,2 H), 7.45-7.52 (m, 2 H), Method A 6.70 (br s, 1 H), 5.44 (br s, 1 H),4.46- 4.57 (m, 2 H), 4.00-4.37 (m, 2 H), 3.24 (dd, 1 H, J = 4.4, 9.8),2.70-3.15 (m, 6 H), 2.15-2.34 (m, 2 H), 1.80- 1.93 (m, 2 H), 1.54-1.63(m, 2 H), 1.25-1.35 (m, 2 H). 478 7 clear oil 519.04 1.12 519.23 ¹H NMR(CDCl₃, 400 MHz) δ 7.71 min 7.84 (m, 2 H), 7.39-7.55 (m, 2 H), Method A6.70 (br m, 1 H), 5.87 (br m, 1 H), 4.88 (m, 1 H), 4.50 (d, 1 H, J =9.5), 4.21-4.31 (m, 2 H), 4.11-4.20 (m, 2 H), 3.80-3.87 (m, 2 H),3.69-3.77 (m, 2 H), 3.31-3.50 (m, 2 H), 3.00- 3.21 (m, 2 H), 2.80-3.95(m, 2 H), 2.10-2.50 (m, 4 H), 1.85-1.95 (m, 2 H), 1.73 (d, 2 H, J =8.5), 1.40-1.50 (m, 2 H) 479 7 clear oil 535.06 1.72 535.18 ¹H NMR(CDCl₃, 400 MHz) δ 7.73 min (d, 2 H, J = 8.6), 7.53 (d, 2 H, J = 8.6),Method A 6.70 (br, s, 1 H), 5.70 (tm, 1 H, J_(HF) = 50), 5.55 (br s, 1H), 4.46 (dd, 1 H, J = 3.8, 10), 3.80-4.00 (m, 3 H), 3.50- 3.70 (m, 1H), 3.15-3.30 (m, 1 H), 2.80-3.95 (m, 1 H), 2.60-2.80 (m, 2 H),2.40-2.60 (m, 1 H), 1.05-2.00 (m, 16 H) 480 1 off-white 444.93 1.89467.09 ¹H NMR (CDCl₃, 400 MHz) δ 7.66 foam min (M + Na⁺) (ddd, 2 H, J =2.0, 2.4, 8.8), 7.44 Method D (ddd, 2 H, J = 2.0, 2.4, 8.8), 7.25-7.31(m, 4 H), 6.30 (br s, 1 H), 5.22 (br s, 1 H), 4.56-4.60 (m, 1 H), 4.47(d, 1 H, J = 15.6), 4.39 (d, 1 H, J = 16.0), 4.32-4.36 (m, 1 H),4.20-4.24 (m, 1 H), 2.23-2.39 (m, 1 H), 1.70-1.85 (m, 1 H), 1.65-1.68(m, 3 H), 1.53 (s, 3 H). 481 6 white 428.87 1.58 429.04 ¹H NMR (CD₃OD,400 MHz) δ 7.92 solid min (d, 2 H, J = 8.4), 7.79 (ddd, 2 H, J = MethodD 2.0, 2.4, 8.8), 7.52 (ddd, 2 H, J = 2.0, 2.8, 8.8), 7.47 (d, 2 H, J =8.0), 4.80 (d, 1 H, J = 16), 4.66 (d, 1 H, J = 14.5), 4.64 (t, 1 H, J =7.6), 4.10-4.33 (m, 2 H), 2.05-2.12 (m, 1 H), 1.72- 1.80 (m, 1 H). 482 6yellow 446.86 1.39 447.06 ¹H NMR (CDCl₃, 400 MHz) δ 7.89 solid min (d, 2H, J = 8.0), 7.66 (dd, 2 H, J = Method B 2.0, 8.0), 7.41 (dd, 2 H, J =2.0, 8.4), 7.31 (d, 2 H, J = 8.0), 6.61 (br s, 1 H), 5.90 (br s, 1 H),5.76 (tm, 1 H, J_(H-F) = 57), 4.56 (d, 1 H, J = 16.0), 4.49-4.52 (m, 1H), 4.36 (d, 1 H, J = 12.0), 2.50- 2.65 (m, 1 H), 1.61-1.70 (m, 1 H).483 6 white 455.94 1.34 488.11 ¹H NMR (CDCl₃, 400 MHz) δ 7.72 solid min(M + Na⁺) (d, 2 H, J = 8.0), 7.68 (d, 2 H, J = 8.0), Method B 7.49 (ddd,2 H, J = 2.0, 2.4, 8.4), 7.38 (d, 2 H, J = 8.0), 6.32 (br s, 1 H), 6.06(br s, 1 H), 5.19 (br s, 1 H), 4.59 (d, 1 H, J = 15.0), 4.56-4.60 (m, 1H), 4.37 (d, 1 H, J = 15.0), 4.29-4.32 (m, 1 H), 4.16-4.19 (m, 1 H),3.45-3.49 (m, 2 H), 2.15-2.30 (m, 1 H), 1.50- 1.65 (m, 1 H), 1.25 (t, 3H, J = 8.0). 484 6 white 469.97 1.40 470.15 ¹H NMR (CDCl₃, 400 MHz) δ7.72 solid min (d, 2 H, J = 8.0), 7.48 (d, 2 H, J = 8.0), Method B7.30-7.36 (m, 4 H), 6.30 (br s, 1 H), 5.26 (br s, 1 H), 4.45-4.58 (m, 2H), 4.38 (d, 1 H, J = 15.2), 4.29-4.32 (m, 1 H), 4.18-4.22 (m, 1 H),3.55-3.59 (m, 1 H), 3.22-3.27 (m, 1 H), 2.90 and 3.05 (2 s, 3 H),2.20-2.33 (m, 1 H), 1.50-1.65 (m, 1 H), 1.08-1.30 (m, 3 H). 485 6 white473.93 1.33 474.11 ¹H NMR (CDCl₃, 400 MHz) δ 7.72 solid min (d, 2 H, J =8.8), 7.70 (d, 2 H, J = 8.4), Method B 7.51 (d, 2 H, J = 8.8), 7.38 (d,2 H, J = 8.0), 6.31 (br s, 1 H), 6.05 (br s, 1 H), 5.72 (tm, 1 H,J_(H-F) = 57), 5.20 (br s, 1 H), 4.59 (d, 1 H, J = 15.6), 4.49-4.52 (m,1 H), 4.31 (d, 1 H, J = 15.6), 3.46- 3.53 (m, 2 H), 2.45-2.65 (m, 1 H),1.57-1.65 (m, 1 H), 1.25 (t, 3 H, J = 7.2). 486 6 white 536.99 1.13537.17 ¹H NMR (CDCl₃, 400 MHz) δ 8.57 solid min (d, 1 H, J = 4.8), 7.83(d, 2 H, J = 8.4), Method B 7.71-7.78 (m, 3 H), 7.71 (br s, 1 H), 7.52(dd, 2 H, J = 1.6, 8.8), 7.40 (d, 2 H, J = 8.0), 7.30-7.35 (m, 1 H),7.23-7.28 (m, 1 H), 6.32 (br s, 1 H), 5.72 (tm, 1 H, J_(H-F) = 57), 5.25(br s, 1 H), 4.75 (d, 2 H, J = 4.8), 4.59 (d, 1 H, J = 15.6), 4.49-4.53(m, 1 H), 4.33 (d, 1 H, J = 15.6), 2.48-2.65 (m, 1 H), 1.58-1.65 (m, 1H). 487 6 white 519.00 1.10 519.35 ¹H NMR (CDCl₃, 400 MHz) δ 8.58 solidmin (d, 1 H, J = 4.4), 7.92 (d, 2 H, J = 8.4), Method B 7.71-7.78 (m, 4H), 7.48 (dd, 2 H, J = 2.0, 8.8), 7.39-7.44 (m, 3 H), 7.24- 7.30 (m, 1H), 6.28 (br s, 1 H), 5.20 (br s, 1 H), 4.78 (d, 2 H, J = 4.8), 4.55-4.61 (m, 2 H), 4.39 (d, 1 H, J = 15.6), 4.29-4.32 (m, 1 H), 4.17-4.21(m, 1 H), 2.20-2.33 (m, 1 H), 1.50-1.65 (m, 1 H). 488 6 white 487.961.63 488.34 ¹H NMR (CDCl₃, 400 MHz) δ 7.72 solid min (dd, 2 H, J = 2.0,8.8), 7.51 (dd, 2 H, J = Method D 2.0, 8.4), 7.50 (s, 4 H), 6.30 (br s,1 H), 5.72 (tm, 1 H, J_(H-F) = 57), 5.24 (br s, 1 H), 4.55 (d, 1 H, J =15.5), 4.49-4.52 (m, 1 H), 4.33 (d, 1 H, J = 15.5), 3.57 (br s, 1 H),3.23 (br s, 1 H), 2.90 and 3.05 (2 s, 3 H), 2.48-2.62 (m, 1 H),1.57-1.72 (m, 1 H), 1.08- 1.30 (m, 3 H). 489 6 off-white 503.96 1.40504.41 ¹H NMR (CDCl₃, 400 MHz) δ 7.72 solid min (d, 4 H, J = 8.4), 7.52(d, 2 H, J = 8.8), Method A 7.38 (d, 2 H, J = 8.4), 6.49 (br s, 1 H),6.31 (br s, 1 H), 5.72 (tm, 1 H, J_(H-F) = 57), 5.19 (br s, 1 H), 4.59(d, 1 H, J = 15.0), 4.48-4.52 (m, 1 H), 4.31 (d, 1 H, J = 15.6),3.62-3.68 (m, 2 H), 3.53-3.59 (m, 2 H), 3.39 (s, 3 H), 2.48-2.62 (m, 1H), 1.57-1.72 (m, 1 H). 490 6 white 485.97 1.27 486.14 ¹H NMR (CDCl₃,300 MHz) δ 7.69- solid min 7.74 (m, 4 H), 7.51 (dd, 2 H, J = 1.8, MethodB 8.4), 7.38 (d, 2 H, J = 8.1), 6.48 (br s, 1 H), 6.32 (br s, 1 H), 5.19(br s, 1 H), 4.54-4.62 (m, 2 H), 4.30-4.41 (m, 2 H), 4.13-4.19 (m, 1 H),3.61-3.67 (m, 2 H), 3.53-3.59 (m, 2 H), 3.39 (s, 3 H), 2.48-2.62 (m, 1H), 1.57-1.72 (m, 1 H). 491 14 off-white 484.91 1.54 485.12 ¹H NMR(CDCl₃, 400 MHz) δ 8.06 solid min (d, 2 H, J = 8.4), 7.74 (d, 2 H, J =8.8), Method B 7.53 (d, 2 H, J = 8.8), 7.48 (d, 2 H, J = 8.4), 6.34 (brs, 1 H), 5.72 (tm, 1 H, J_(H-F) = 57), 5.20 (br s, 1 H), 4.65 (d, 1 H, J= 15.4), 4.51-4.56 (m, 1 H), 4.33 (d, 1 H, J = 15.8), 2.48-2.65 (m, 1H), 2.47 (s, 3 H), 1.57-1.65 (m, 1 H). 492 14 off-white 466.92 1.65467.19 ¹H NMR (CDCl₃, 400 MHz) δ 8.04 solid min (d, 2 H, J = 8.0), 7.74(dd, 2 H, J = Method A 1.6, 8.4), 7.48-7.51 (m, 4 H), 6.32 (br s, 1 H),5.17 (br s, 1 H), 4.65 (d, 1 H, J = 16.0), 4.56-4.60 (m, 1 H), 4.40 (d,1 H, J = 16.0), 4.29-4.32 (m, 1 H), 4.18-4.21 (m, 1 H), 2.47 (s, 3 H),2.18-2.38 (m, 1 H), 1.50-1.65 (m, 1 H). 493 6 white 478.88 1.59 479.15¹H NMR (dmso-d₆, 400 MHz) δ 7.88 solid min (d, 2 H, J = 8.0), 7.85 (d, 2H, J = 8.8), Method A 7.63 (d, 2 H, J = 8.8), 7.51 (d, 2 H, J = 8.0),7.42 (br s, 1 H), 7.24 (br s, 1 H), 4.77 (d, 2 H, J = 2.0), 4.40-4.44(m, 1 H), 1.97-2.05 (m, 2 H), 1.75-1.84 (m, 1 H), 1.42-1.50 (m, 1 H).494 1 white 492.91 1.66 493.11 ¹H NMR (CDCl₃, 400 MHz) δ 7.97 solid min(d, 2 H, J = 8.4), 7.69 (dd, 2 H, J = Method A 1.6, 8.4), 7.50 (dd, 2 H,J = 2.0, 8.4), 7.40 (d, 2 H, J = 8.4), 6.22 (br s, 1 H), 5.19 (br s, 1H), 4.58 (d, 1 H, J = 16.0), 4.43 (d, 1 H, J = 15.6), 4.31- 4.35 (m, 1H), 3.91 (s, 3 H), 2.08-2.20 (m, 1 H), 1.88-2.03 (m, 1 H), 1.69- 1.82(m, 1 H), 1.38-1.47 (m, 1 H). 495 6 off-white 519.97 1.48 520.21 ¹H NMR(CDCl₃, 400 MHz) δ 7.70 solid min (d, 2 H, J = 8.4), 7.50 (d, 2 H, J =8.8), Method B 7.37 (d, 2 H, J = 8.4), 7.33 (d, 2 H, J = 8.0), 6.20 (brs, 1 H), 5.26 (br s, 1 H), 4.45-4.52 (m, 2 H), 4.33 (t, 1 H, J = 7.2),3.61-3.70 (m, 1 H), 3.22-3.27 (m, 1 H), 2.90 and 3.06 (2 s, 3 H),2.05-2.18 (m, 1 H), 1.90-2.03 (m, 1 H), 1.69-1.82 (m, 1 H), 1.38-1.47(m, 1 H), 1.11-1.28 (m, 3 H). 496 6 off-white 569.01 1.21 569.16 ¹H NMR(CDCl₃, 400 MHz) δ 8.57 solid min (d, 1 H, J = 4.8), 7.82 (d, 2 H, J =8.4), Method B 7.68-7.72 (m, 4 H), 7.50 (d, 2 H, J = 8.8), 7.42 (d, 2 H,J = 8.4), 7.35 (d, 1 H, J = 8.0), 7.24 (br s, 1 H), 6.24 (br s, 1 H),5.26 (br s, 1 H), 4.76 (d, 2 H, J = 4.8), 4.58 (d, 1 H, J = 15.6), 4.41(d, 1 H, J = 15.6), 4.31-4.35 (m, 1 H), 2.10-2.19 (m, 1 H), 1.90-2.03(m, 1 H), 1.69-1.82 (m, 1 H), 1.38-1.47 (m, 1 H). 497 6 white 535.971.53 536.16 ¹H NMR (CDCl₃, 400 MHz) δ 7.72 solid min (d, 2 H, J = 8.0),7.69 (d, 2 H, J = 8.4), Method A 7.50 (d, 2 H, J = 8.4), 7.40 (d, 2 H, J= 8.4), 6.48 (br s, 1 H), 6.22 (br s, 1 H), 5.20 (br s, 1 H), 4.57 (d, 1H, J = 15.6), 4.41 (d, 1 H, J = 15.6), 4.30- 4.34 (m, 1 H), 3.63-3.67(m, 2 H), 3.55-3.57 (m, 2 H), 3.39 (s, 3 H), 2.10-2.20 (m, 1 H),1.88-2.03 (m, 1 H), 1.69-1.82 (m, 1 H), 1.38-1.47 (m, 1 H). 498 6 white505.95 1.55 506.10 ¹H NMR (CDCl₃, 400 MHz) δ 7.69 solid min (dd, 2 H, J= 1.6, 8.4), 7.50 (d, 2 H, J = Method A 8.4), 7.39 (d, 2 H, J = 8.0),7.25- 7.28 (m, 2 H), 6.22 (br s, 1 H), 4.57 (d, (br s, 1 H), 5.19 (br s,1 H), 4.57 (d, 1 H, J = 15.6), 4.41 (d, 1 H, J = 15.6), 4.30-4.33 (m, 1H), 3.48-3.53 (m, 2 H), 2.10-2.20 (m, 1 H), 1.88-2.03 (m, 1 H),1.69-1.82 (m, 1 H), 1.38- 1.47 (m, 1 H), 1.35 (t, 3 H, J = 7.2). 499 14Beige 516.93 1.65 517.15 ¹H NMR (CDCl₃, 400 MHz) δ 8.06 solid min (dd, 2H, J = 1.6, 8.4), 7.71 (dd, 2 H, J = Method B 2.0, 8.4), 7.49-7.52 (m, 4H), 6.22 (br s, 1 H), 5.20 (br s, 1 H), 4.63 (d, 1 H, J = 15.6), 4.44(d, 1 H, J = 15.6), 4.33-4.37 (m, 1 H), 2.47 (s, 3 H), 2.10-2.20 (m, 1H), 1.91-2.03 (m, 1 H), 1.73-1.86 (m, 1 H), 1.40-1.51 (m, 1 H). 500 1off-white 494.94 1.74 475.27 ¹H NMR (CDCl₃, 500 MHz) δ 7.65 foam min (M− (dd, 2 H, J = 2.0, 8.5), 7.46 (ddd, 2 H, Method B HF + J = 2.0, 2.5,7.5), 7.25-7.31 (m, 4 H), H+) 6.18 (br s, 1 H), 5.24 (br s, 1 H), 4.47(d, 1 H, J = 15.5), 4.41 (d, 1 H, J = 15.0), 4.35 (t, 1 H, J = 7.7),2.08-2.20 (m, 1 H), 1.88-2.03 (m, 1 H), 1.69- 1.82 (m, 1 H), 1.68 (s, 3H), 1.63 (s, 3 H), 1.38-1.47 (m, 1 H). 501 12 off-white 492.95 2.20475.96 ¹H NMR (CDCl₃, 400 MHz) δ 7.65 solid min (—H₂O) (d, 2 H, J =8.8), 7.46 (d, 2 H, J = 8.4), Method A 492.01 7.40 (d, 2 H, J = 8.4),7.25-7.27 (m, (neg ion) 2 H), 6.19 (br s, 1 H), 5.23 (br s, 1 H), 4.46(d, 1 H, J = 15.4), 4.41 (d, 1 H, J = 15.4), 4.34 (t, 1 H, J = 7.6),2.08- 2.20 (m, 1 H), 1.88-2.03 (m, 1 H), 1.69-1.82 (m, 1 H), 1.56 (s, 3H), 1.54 (s, 3 H), 1.38-1.47 (m, 1 H).Method A = 4.6 × 33 mm ODS-A C-18 column, 5 mL/min, 10:90:0.1(MeOH/H₂O/TFA) to 90:10:0.1 (MeOH/H₂O/TFA), 2 min gradientMethod B = 3 × 50 mm ODS-A C-18 column, 5 mL/min, 10:90:0.1(MeOH/H₂O/TFA) to 90:10:0.1 (MeOH/H₂O/TFA), 2 min gradientMethod C = 3 × 50 mm ODS-A C-18 column, 5 mL/min, 10:90:0.1(MeOH/H₂O/TFA) to 90:10:0.1 (MeOH/H₂O/TFA), 3 min gradientMethod D = 4.6 × 50 mm Phenomenex Luna C-18 S5 column, 5 mL/min, 0-100%MeOH/H₂O, 0.1% TFA, 2 min gradientMethod E = 4.6 × 50 mm Xterra C18 S5 column, 5 mL/min, 0-100% MeOH/H₂O,0.1% TFA, 2 min gradientMethod F = 4.6 × 50 mm Phenomenex Luna C-18 S5 column, 5 mL/min,10:90:0.1 (MeOH/H₂O/TFA) to 90:10:0.1 (MeOH/H₂O/TFA), 2 min gradientMethod G = 3.0 × 50 mm Xterra C18 S7 column, 5 mL/min, 10:90:0.1(MeOH/H₂O/TFA) to 90:10:0.1 (MeOH/H₂O/TFA), 2 min gradient

1. A method for the treatment of Alzheimer's disease in a mammal in needthereof, which comprises administering to said mammal a therapeuticallyeffective amound of a compound formula I; or an optical isomer thereof

wherein: R¹ is selected from the group consisting of (a) a straight orbranched-chain C₁₋₆ alkyl or C₂₋₆alkenyl optionally substituted withsubstituents selected from the group consisting of hydroxy, C₃₋₇cycloalkyl, C₁₋₄alkoxy, C₁₋₄alkylthio, and halogen; (b) C₃₋₇ cycloalkyloptionally substituted with hydroxy or halogen; R is hydrogen or R¹ andR taken together is C₂₋₅alkylene; R² is selected from the groupconsisting of (a) a straight or branched-chain C₁₋₆alkyl or C₃₋₆alkenyloptionally substituted with substituents selected from the groupconsisting of halogen, C₁₋₄alkoxy, and NR⁴R⁵; (b) C₃₋₇ cycloalkylmethyloptionally substituted with substituents selected from the groupconsisting of amino, (C₁₋₄alkyl)NH—, di(C₁₋₄alkyl)N—,C₁₋₁₄alkylC(═O)NH—, and C₁₋₁₄alkylOC(═O)NH—; (c) a straight orbranched-chain C₁₋₆alkyl-C(═O)-A; (d) —B-naphthyl; (e)

D and E are each independently a direct bond, a straight orbranched-chain C₁₋₆alkyl, C₂₋₆ alkenyl, or C₃₋₇ cycloalkyl; Z isselected from the group consisting of hydrogen, C₁₋₄alkyl, C₁₋₄alkoxy,halogen, cyano, hydroxy, —OCHF₂, —OCF₃, —CF₃, and —CHF₂; X and Y areeach independently selected from the group consisting of hydrogen,hydroxy, halogen, (halogen)₃C—, (halogen)₂CH—, C₁₋₁₄alkylS—,C₁₋₄alkylS(O)—, C₁₋₄alkylSO₂—, nitro, F₃S—, and cyano; —OR⁶; —NR⁴R⁵;—NR⁷C(═O)R⁸; —NR⁷C(═O)OR⁸; —NHSO₂C₁₋₄alkyl; —N(SO₂C₁₋₄alkyl)₂; —C(═O)Wwherein W is selected from the group consisting of hydroxy, C₁₋₄alkyl,C₁₋₄alkoxy, phenoxy, and —NR⁴R⁵; —OC(═O)C₁₋₄alkyl; -phenyl in which saidphenyl is optionally substituted with cyano, halogen, C₁₋₄alkoxy,C₁₋₁₄alkylS—, CH₃C(═O), C₁₋₁₄alkylS(O)—, or C₁₋₄alkylSO₂—; andheterocyclic group, in which said heterocyclic group is selected fromthe group consisting of furanyl, thiofuranyl, pyrrolyl, imidazolyl,pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, oxadiazolyl,oxazolyl, isoxazolyl, thiadiazolyl, and thiazolyl, wherein saidheterocyclic group is optionally substituted with substituents selectedfrom the group consisting of cyano, halogen, C₁₋₄alkyl,(halogen)C₁₋₄alkyl, and CO₂C₁₋₄alkyl; (f) —B-(heterocycle), in whichsaid heterocycle is selected from the group consisting of furanyl,thiofuranyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl,pyridinyl, pyrimidinyl, oxadiazolyl, oxazolyl, isoxazolyl, thiadiazolyland thiazolyl wherein said heterocycle is optionally substituted withsubstituents selected from the group consisting of cyano, halogen,C₁₋₁₄alkyl, CO₂C₁₋₁₄alkyl, amino, (C₁₋₁₄alkyl)NH—, di(C₁₋₄alkyl)N—,morpholin-4-yl, thiomorpholin-4-yl, pyrrolidin-1-yl, piperidin-1-yl,piperazin-1-yl, and 4-(C₁₋₆alkyl)piperazin-1-yl; (g)—B-(piperidin-4-yl), in which said piperidin-4-yl is optionallysubstituted with substituents selected from the group consisting of astraight or branched-chain C₁₋₆alkyl, CH₂C(═O)phenyl, phenyl andphenylmethyl in which said C₁₋₆alkyl and said phenyl are optionallysubstituted with substituents selected from the group consisting ofcyano, halogen, benzimidazol-2-yl, pyridyl and tetrahydrofuran-2-yl; and—C(═O)W′ wherein W′ is selected from the group consisting of C₁₋₄alkoxy,R⁹, and —NR⁴R⁵; A is hydroxy, C₁₋₄alkoxy or NR⁴R⁵; B is a straight orbranched-chain C₁₋₆alkyl or C₃₋₆alkenyl; R³ is phenyl or pyridyloptionally substituted with substituents selected from the groupconsisting of halogen, hydroxy, C₁₋₄alkoxy, C₁₋₄alkyl, (halogen)₃C—,(halogen)₂CH—, and halogenCH₂—; R⁴ and R⁵ each are independentlyhydrogen, a straight or branched-chain C₁₋₆ alkyl, C₃₋₆ alkenyl, C₃₋₆alkynyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylmethyl, C₁₋₄alkoxy, phenyl,benzyl, pyridyl, piperidin-4-yl, indan-1-yl, indan-2-yl,tetrahydrofuran-3-yl, or pyrrolidin-3-yl; in which each is optionallysubstituted with substituents selected from the group consisting ofhydroxy, cyano, halogen, (halogen)₃C—, (halogen)₂CH—, halogenCH₂—,hydroxymethyl, benzyloxymethyl, phenyl, pyridyl, C₁₋₄alkyl, C₁₋₄alkoxy,(halogen)₃C—O—, (halogen)₂CH—O—, C₁₋₄alkylthio, amino, (C₁₋₄alkyl)NH—,di(C₁₋₄alkyl)N—, morpholin-4-yl, thiomorpholin-4-yl, pyrrolidin-1-yl,piperidin-1-yl, piperazin-1-yl, 4-(C₁₋₆alkyl)piperazin-1-yl,4-phenylpiperazin-1-yl, 4-benzylpiperazin-1-yl, 4-pyridylpiperazin-1-yl,CO₂H, CO₂C₁₋₄alkyl, C(═O)NHC₁₋₄alkyl, and C(═O)N(C₁₋₄alkyl)₂; R⁴ and R⁵taken together may be morpholin-4-yl, thiomorpholin-4-yl,pyrrolidin-1-yl, 1,2,3,4-tetrahydroisoquinolin-2-yl,decahydroquinolin-1-yl, piperidin-1-yl, piperazin-1-yl,[1,4]-oxazepan-4-yl, azetidin-1-yl, 2,3-dihydro-1H-isoindol-2-yl, or2,3-dihydro-1H-indol-1-yl; in which each is optionally substituted withsubstituents selected from the group consisting of hydroxy, cyano,halogen, (halogen)₃C—, (halogen)₂CH—, halogenCH₂—, phenyl, pyridyl,benzyl, C₁₋₆alkyl, C₃₋₇ cycloalkyl, C₁₋₄alkoxy, C₁₋₄alkylthio, amino,(C₁₋₄alkyl)NH—, di(C₁₋₄alkyl)N—, CO₂H, CO₂C₁₋₄alkyl, C(═O)NHC₁₋₄alkyl,and C(═O)N(C₁₋₄alkyl)₂; R⁶ is a straight or branched-chain C₁₋₆alkyl,C₃₋₆ alkenyl, benzyl, or phenyl in which each is optionally substitutedwith substituents selected from the group consisting of halogen,C₁₋₄alkyl, C₁₋₁₄alkoxy, amino, (C₁₋₄alkyl)NH—, di(C₁₋₄alkyl)N—,(C₁₋₄alkyl)(phenyl)N—, morpholin-4-yl, thiomorpholin-4-yl,pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, and4-(C₁₋₆alkyl)piperazin-1-yl; R⁷ is hydrogen, a straight orbranched-chain C₁₋₆ alkyl; R⁸ is a straight or branched-chain C₁₋₆alkyl,C₃₋₇ cycloalkyl, phenyl, pyridyl, or furanyl; in which each isoptionally substituted with substituents selected from the groupconsisting of halogen, C₁₋₄alkyl, C₁₋₄alkoxy, (C₁₋₄alkyl)NH—,di(C₁₋₄alkyl)N—, morpholin-4-yl, thiomorpholin-4-yl, pyrrolidin-1-yl,piperidin-1-yl, piperazin-1-yl, and 4-(C₁₋₆alkyl)piperazin-1-yl; R⁹ is astraight or branched-chain C₁₋₆alkyl, C₃₋₆ alkenyl, benzyl, phenyl,oxazolyl or pyridyl; in which each is optionally substituted withsubstituents selected from the group consisting of halogen,(halogen)₃C—, (halogen)₂CH—, halogenCH₂—, C₁₋₄alkyl, C₁₋₄alkoxy, amino,(C₁₋₄alkyl)NH—, di(C₁₋₄alkyl)N—, morpholin-4-yl, thiomorpholin-4-yl,pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, and4-(C₁₋₆alkyl)piperazin-1-yl; or a non-toxic pharmaceutically acceptablesalt thereof.